Inhibitors of human immunodeficiency virus replication

ABSTRACT

Compounds of Formula I, including pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth:

FIELD OF THE INVENTION

The invention relates to compounds, compositions, and methods for thetreatment of human immunodeficiency virus (HIV) infection. Moreparticularly, the invention provides novel Capsid inhibitors,pharmaceutical compositions containing such compounds, and methods forusing these compounds in the treatment of HIV infection. The inventionalso relates to methods for making the compounds hereinafter described.

BACKGROUND OF THE INVENTION

Acquired immunodeficiency syndrome (AIDS) is the result of infection byHIV. HIV continues to be a major global public health issue. In 2015, anestimated 36.7 million people were living with HIV (including 1.8million children)—a global HIV prevalence of 0.8%. The vast majority ofthis number live in low- and middle-income countries. In the same year,1.1 million people died of AIDS-related illnesses.

Current therapy for HIV-infected individuals consists of a combinationof approved anti-retroviral agents. Close to four dozen drugs arecurrently approved for HIV infection, either as single agents, fixeddose combinations or single tablet regimens; the latter two containing2-4 approved agents. These agents belong to a number of differentclasses, targeting either a viral enzyme or the function of a viralprotein during the virus replication cycle. Thus, agents are classifiedas either nucleotide reverse transcriptase inhibitors (NRTIs),non-nucleotide reverse transcriptase inhibitors (NNRTIs), proteaseinhibitors (PIs), integrase strand transfer inhibitors (INSTIs), orentry inhibitors (one, maraviroc, targets the host CCR5 protein, whilethe other, enfuvirtide, is a peptide that targets the gp41 region of theviral gp160 protein). In addition, a pharmacokinetic enhancer(cobicistat or ritonavir) can be used in combinations withantiretroviral agents (ARVs) that require boosting.

Despite the armamentarium of agents and drug combinations, there remainsa medical need for new anti-retroviral agents. High viral heterogeneity,drug-associated toxicity, tolerability problems, and poor adherence canall lead to treatment failure and may result in the selection of viruseswith mutations that confer resistance to one or more antiretroviralagents or even multiple drugs from an entire class (Beyrer, C., PozniakA. HIV drug resistance—an emerging threat to epidemic control. N. Engl.J. Med. 2017, 377, 1605-1607; Gupta, R. K., Gregson J., et al. HIV-1drug resistance before initiation or re-initiation of first-lineantiretroviral therapy in low-income and middle-income countries: asystematic review and meta-regression analysis. Lancet Infect. Dis.2017, 18, 346-355; Zazzi, M., Hu, H., Prosperi, M. The global burden ofHIV-1 drug resistance in the past 20 years. PeerJ. 2018, DOI10.7717/peerj.4848). As a result, new drugs are needed that are easierto take, have high genetic barriers to the development of resistance andhave improved safety over current agents. In this panoply of choices,novel mechanisms of action (MOAs) that can be used as part of thepreferred antiretroviral therapy (ART) can still have a major role toplay since they should be effective against viruses resistant to currentagents.

Certain potentially therapeutic compounds have now been described in theart and set forth in Blair, Wade S. et.al. Antimicrobial Agents andChemotherapy (2009), 53(12), 5080-5087, Blair, Wade S. et al. PLoSPathogens (2010), 6(12), e1001220, Thenin-Houssier, Suzie; Valente,Susana T. Current HIV Research, 2016, 14, 270-282, and PCT Patentapplications with the following numbers: WO 2012065062, WO 2013006738,WO 2013006792, WO 2014110296, WO 2014110297, WO 2014110298, WO2014134566, WO 2015130964, WO2015130966, WO 2016033243, W02018035359,W02018203235, WO 2019161017, and WO 2019161280.

What is now needed in the art are additional compounds which are noveland useful in the treatment of HIV. Additionally, these compounds shouldprovide advantages for pharmaceutical uses, for example, with regard toone or more of their mechanisms of action, binding, inhibition efficacy,target selectivity, solubility, safety profiles, bioavailability orreduced frequency of dosing. Also needed are new formulations andmethods of treatment which utilize these compounds.

SUMMARY OF THE INVENTION

Briefly, in one aspect, the present invention discloses a compound ofFormula I, or a pharmaceutically acceptable salt thereof:

wherein:X¹ and X² are independently selected from H, F, Cl or —CH₃ and X³ is H,F, Cl, —CH_(3,) —OCH₃, —OCHF₂, or —OCF₃ with the proviso that within thegroup X¹, X², and X³ the substituent Cl is not used more than twice andthe substituent —CH₃ is not used more than twice;Q is selected from:

R¹ is H, Cl, or CH₃;R² is H, C₁-C₃alkyl optionally substituted with 1-3 fluorines, orC₃-C₆cycloalkyl optionally substituted with 1-2 fluorines;R³ is C₁-C₃alkyl or C₃-C₄cycloalkyl;G^(1a) is phenyl, pyridine, pyrazine, or pyrimidine, each of which issubstituted with —SF₅, or G^(1a) is selected from:

G² is C₁-C₃alkyl, —O(C₁-C₃alkyl), —S(O₂)CH₃, or —C(CH₃)₂OH whereinC₁-C₃alkyl is optionally substituted with 1-3 fluorines;G³ is H, or methyl optionally substituted with 1-3 fluorines;G⁴ and G⁵ are independently selected from H, —O(C₁-C₃alkyl), orC₁-C₂alkyl optionally substituted with 1-3 fluorines;

G⁶ is H, Cl, or F;

G⁷ is H, —OCH₃, or —S(O₂)CH₃;G⁸ is H, methyl, ethyl, or Cl;

G⁹ is H or Cl;

G¹⁰ is H, C₁-C₂alkyl, —OCH₃, or —SF₅ where C₁-C₂alkyl is optionallysubstituted with 1-3 fluorines;G¹¹ and G¹² are independently selected from H, F, Cl or C₁-C₂alkylwherein C₁-C₂alkyl are optionally substituted with 1-3 fluorines;

G¹³ is H or F;

G¹⁴ is H, methyl, Cl, —OCH₃;G¹⁵ is —O(C₁-C₂alkyl) substituted with 1-3 fluorines, or —S(O₂)CH₃;G¹⁶ is C₁-C₂alkyl substituted with 1-3 fluorines, or —O(C₁-C₂alkyl)wherein substituted with 1-3 fluorines;G¹⁷ is H, cPr, —CH2cPr, or C₁-C₄alkyl wherein C₁-C₄alkyl is optionallysubstituted with 1-5 fluorines;

Y is O, S or N;

G^(1b) is pyridine, pyrimidine, pyrazine, or phenyl, each of which issubstituted once from the group F, Cl, or C₁-C₂alkyl wherein C₁-C₂alkylis optionally substituted with 1-3 fluorines;W is selected from:

wherein R⁴ is methyl optionally substituted with 1-3 fluorines.

In another aspect, the present invention discloses a compositioncomprising a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention discloses a method of treatingHIV infection in a human comprising administering a compound of FormulaI or a pharmaceutically acceptable salt thereof to a patient.

In another aspect, the present invention discloses a compound of FormulaI or pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, the present invention discloses a compound of FormulaI or pharmaceutically acceptable salt thereof for use in treating HIVinfection in a human. In another aspect, the present invention disclosesthe use of a compound of Formula I or pharmaceutically acceptable saltthereof in the manufacture of a medicament for the treatment of HIVinfection in a human.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein Q is:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein Q is:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein W is:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein W is:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein W is thefollowing:

wherein R⁴ is methyl optionally substituted with 1-3 fluorines.

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein R¹ is Cl; R² ismethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl; and R³ is methyl orcyclopropyl.

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein R¹ is Cl; R² ismethyl; and R³ is methyl.

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein X³ is H. Inanother embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein X¹ is F, X² isF, and X³ is H. In another embodiment, the present invention disclosescompounds of Formula I and pharmaceutically acceptable salts thereofwherein if X³ is H then at least one of X¹ and X² is other than F.

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1b) is one ofthe following:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein G^(1a) or G^(1b)contains 2-3 fluorines.

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein the chemicalformula of G^(1a) or G^(1b) is C₍₄₋₆₎H₍₂₋₃₎F₍₂₋₃₎N₍₁₋₂₎.

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein thestereochemistry is as depicted below:

In one embodiment, the present invention discloses compounds of FormulaI and pharmaceutically acceptable salts thereof wherein thestereochemistry is as depicted below:

In one embodiment, the present invention discloses compounds and saltsselected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention discloses compounds and saltsselected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention discloses compounds and saltsselected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention discloses compounds and saltsselected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention discloses compounds and saltsselected from the group consisting of:

and pharmaceutically acceptable salts thereof.

The salts of the invention are pharmaceutically acceptable. Such saltsmay be acid addition salts or base addition salts. For a review ofsuitable pharmaceutically acceptable salts see, for example, Berge etal, J. Pharm, Sci., 66, 1-19, 1977.

Representative pharmaceutically acceptable acid addition salts include,but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate,bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate(camsylate), caprate (decanoate), caproate (hexanoate), caprylate(octanoate), cinnamate, citrate, cyclamate, digluconate,2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate(ethylenediaminetetraacetate), estolate (lauryl sulfate),ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate,fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate),glucoheptonate (gluceptate), gluconate, glucuronate, glutamate,glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate,hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide,hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate,lactobionate, laurate, malate, maleate, malonate, mandelate,methanesulfonate (mesylate), methylsulfate, mucate,naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate(napsylate), nicotinate, nitrate, oleate, palmitate,p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate),pantothenate, pectinate, persulfate, phenylacetate,phenylethylbarbiturate, phosphate, polygalacturonate, propionate,p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate,sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate,tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide,undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include,but are not limited to, aluminium,2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine),arginine, benethamine (N-benzylphenethylamine), benzathine(N,N′-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth,calcium, chloroprocaine, choline, clemizole (1-pchlorobenzyl-2-pyrrolildine-1′-ylmethylbenzimidazole), cyclohexylamine,dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine,dimethylethanolamine, dopamine, ethanolamine, ethylenediamine,L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium,meglumine (N-methylglucamine), piperazine, piperidine, potassium,procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

In one embodiment, the compositions of this invention further comprise apharmaceutically acceptable excipient. In the method of this invention,preferred routes of administration are oral and by injection to deliversubcutaneously or intramuscularly. Therefore, preferred pharmaceuticalcompositions include compositions suitable for oral administration (forexample tablets) and compositions suitable for subcutaneous orintramuscular injection.

In another aspect the present invention discloses methods of preventingHIV infection in a human or reducing the risk of infection, comprisingadministering a compound or salt of this invention. Pre-exposureprophylaxis (or PrEP) is when people at risk for HIV infection takedaily medicine to lower their chances of getting HIV infection. PrEP hasbeen shown to be effective in reducing the risk of infection. As usedherein, “HIV” or “Human Immunodeficiency Virus” refers to HIV-1 and/orto HIV-2.

The compounds and salts of this invention are believed to have as theirbiological target the HIV capsid and thus their mechanism of action isto modify in one or more ways the function of the HIV capsid.

The compounds and salts of the present invention may be employed aloneor in combination with other therapeutic agents. Combination therapiesaccording to the present invention thus comprise the administration ofat least one compound or salt of the invention, and the administrationof at least one other agent which may be useful in the treatment of HIVinfection. A compound or salt of the present invention, and the otheragent may be formulated and administered together in a singlepharmaceutical composition or may be formulated and administeredseparately. When formulated and administered separately, administrationmay occur simultaneously or sequentially in any order. Suitable otheragents include, for example, abacavir, atazanavir, bictegravir,cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine,dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine,etavirine, fosamprenavir, fostemsavir, GSK3640254, the antibody N6LS,GSK3739937/VH3739937 and GSK4000422/VH4000422, indinavir, lamivudine,lopinavir, maraviroc, nelfinavir, nevirapine, raltegravir, rilpiverine,ritonavir, saquinavir, slatravir, stavudine, tipranavir, tenofovir,tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine,zidovudine, and S-648414. Preferred agents include, for example,bictegravir, cabotegravir, dolutegravir, fostemsavir, islatravir, andlamivudine. Particularly preferred agents include, for example,bictegravir, cabotegravir, dolutegravir, fostemsavir, and lamivudine.

EXAMPLES General Procedures General Procedure B:

A 5 mL microwave vial was charged with(3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (0.047-0.093 mmol, 1 equiv.), the indicatedstannane (1.0-1.2 equiv), and Pd(PPh₃)₄ (0.10 equiv.). To the mixturewas added degassed (sparged with nitrogen gas for 2 minutes)N,N-Dimethylformamide (1 mL). The mixture was stirred and purged withnitrogen for 2 min. The vial was capped and the mixture was then heatedat 100° C. for 18 h. The reaction mixture was diluted with water andextracted with EtOAc, dried over Na₂SO₄ and concentrated in vacuo. Theresulting residue was subjected to silica gel chromatography (12 g or 24g column) using 5-100% ethyl acetate in hexanes and then 100% ethylacetate. The desired fractions were pooled and then concentrated underreduced pressure to afford a solid (typically purple or yellow). Thesolid was taken up in DCM (1 mL): TFA (0.5 mL) and to the solution wasadded triflic acid (3 equiv.). The resultant purple solution was stirredat RT for 30-60 min and then was concentrated in vacuo. The residue wastaken up in ethyl acetate. The pH was adjusted to pH>7 using aq. 1 NNaOH. The mixture was dried over Na₂SO₄, filtered, and then concentratedin vacuo. The resulting residue was dissolved in DMF, the mixture wasfiltered, and the filtrate was subjected to prep-HPLC purification toafford the indicated product.

General Procedure E:

To 5 mL vial equipped with a stir bar was added a solution of(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (30 mg, 0.031 mmol) in THF (1.0 mL), asolution of K₃PO₄ (0.025 g, 0.094 mmol) in water (0.25 mL),dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(2.377 mg, 3.14 μmol), and the appropriate boronic acid (0.094 mmol).The vial was degassed (the flask was evacuated and the atmospherereplaced with Ar; this process repeated three time) and then maintainedunder Ar atmosphere. The mixture was stirred at rt for 16 h. To themixture was added 2 M ammonia in methanol (1 mL). The mixture wasstirred for 2 h and then concentrated under reduced pressure. Theresulting residue was dissolved in DMF, the solution was filtered, andthe filtrate was subjected to prep-HPLC purification to afford theproduct as indicated.

General Procedure F:

A 5 mL microwave vial was charged withN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(0.042 g, 0.035 mmol), the appropriate halide (0.104 mmol), copper(I)iodide (0.658 mg, 3.46 μmol) and Pd(PPh₃)₄ (3.99 mg, 3.46 μmol). To themixture was added degassed (bubbled with nitrogen gas for 2 minutes)N,N-Dimethylformamide (1 mL). The mixture was stirred and purged withnitrogen for 2 min. The vial was capped and heated at 100° C. for 18 h.The reaction mixture was diluted with water and extracted with EtOAc,dried over Na₂SO₄ and concentrated under reduced pressure. The resultingresidue was purified by silica gel chromatography (24 g RediSep Goldcolumn) using 0-70% ethyl acetate in hexanes over 10 CV, then at 70%EtOAc in hexanes over 5 CV. The desired fractions were pooled andconcentrated to afford a yellow solid. The solid was taken up in DCM (1mL):TFA (0.5 mL) and to the solution was added triflic acid (0.016 mL,0.182 mmol). The resulting purple solution was stirred for 30 min andthen concentrated in vacuo. The residue was taken up in ethyl acetateand the pH was then adjusted to pH>7 by the addition of aq. 1N NaOH. Themixture was dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresulting residue was dissolved in DMF, the solution was filtered, andthe filtrate was subjected to prep-HPLC purification to afford theindicated product.

General Procedure G:

A 5 mL microwave vial was charged with the indicated stannane (0.068mmol)),(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-y)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (0.05 g, 0.052 mmol), and Pd(PPh₃)₄ (6.06 mg,5.24 μmol). To the mixture was added degassed (bubbled with nitrogen gasfor 2 minutes) N,N-Dimethylformamide (1 mL). The mixture was stirred andpurged with nitrogen for 2 min. The vial was capped and heated at 100°C. for 18 h. The reaction mixture was diluted with DMF(1 mL), filtered,and the filtrate was subjected to prep-HPLC purification to afford theindicated product.

General Procedure H:

In a 5 mL microwave vial equipped with a stir bar were combinedN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1 equiv, typically 0.032-0.041 mmol), Pd(PPh₃)₄ (0.1 equiv), copper(I)iodide (0.1 equiv), the indicated halo-heterocycle (3 equiv), and DMF(0.03M relative to stannane). The vial was sealed with a septum cap andthen was placed under Ar atmosphere (vacuum evacuation followed byrefill with Ar, repeated 3 times). The vial was placed in a 100° C.heating block upon which the yellow solution quickly turned brown andthen black. The mixture was stirred at 100° C. for 30-60 min. Thereaction mixture was diluted with DMF (up to 2 mL), then filtered, andthe filtrate was subjected to HPLC purification to afford the indicatedproduct.

General Procedure J:

In a 5 mL microwave vial was combined(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (1 equiv, typically 0.031-0.037 mmol),copper(I) iodide (0.1 equiv), Pd(PPh₃)₄ (0.1 equiv), the indicatedstannane (3 equiv) and DMF (0.1M relative to trifluoromethanesulfonate).The vial was purged with N₂ gas and then was capped with a septum cap.The vial was placed in a 100° C. reaction block with stirring for 15-60min (reaction progress monitored by LCMS). The reaction solution wascooled to r.t. and then was subjected to HPLC purification to afford theindicated product.

General Procedure K:

In a dry 1 dram vial equipped with a stir bar was combined(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (or other coupling partner as indicated) (1equiv, typically 0.028-0.037 mmol), tribasic potassium phosphate (3equiv),dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(0.05-0.1 equiv) and the indicated boronic acid or boronic ester (2-3equiv). The vial was purged with argon and then was sealed with a septumcap. To the vial was added THF:water (4:1, 0.05M relative totrifluoromethanesulfonate). The mixture was stirred at either ambienttemperature or 60° C. for 1-18 h (typically 18 h). Upon cooling toambient temperature, the reaction was concentrated and the residue wassubjected to HPLC purification to afford the indicated product.

General Procedure M:

To a solution ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(or other pyrazole as indicated) (25 mg, 0.025 mmol) and the indicatedtriflate (0.076 mmol) in acetonitrile (1 mL) was added cesium carbonate(12.31 mg, 0.038 mmol). The resulting mixture was heated at 50° C. for 1h, then the mixture was then cooled to room temperature, filtered andconcentrated under reduced pressure. The resulting residue was taken upin DCM (0.5 mL) and to the mixture was added TFA (1 mL) and then triflicacid (0.05 mL). The mixture was stirred at rt for 1 h and then wasconcentrated in vacuo. The resulting residue was then taken up in DMF (2mL), filtered, and the filtrate was subjected to HPLC purification toafford the indicated product.

General LCMS Analysis Methods LCMS Method A:

Column=Acquity UPLC BEH C18, 2.1×30 mm, 1.7 μm particles; Solvent A=0.1%Formic acid in 100% Water; Solvent B=0.1% Formic Acid in 100%Acetonitrile; Flow Rate=0.8 mL/min.; Start % B=5, Final % B=95; GradientTime=1.6 min, then a 0.25 min hold at 95% B. Detection=215 nm.

LCMS Method B:

Column=Acquity BEH C18, 2.1×30 mm, 1.7 μm particles; Solvent A=0.1%Formic acid in 100% Water; Solvent B=0.1% Formic Acid in 100%Acetonitrile; Flow Rate=0.8 mL/min.; Start % B=5, Final % B=95; GradientTime=1.7 min, then a 0.2 min hold at 95% B. Detection=215 and 254 nm.

LCMS Method D:

Column: Acquity UPLC BEH C18, 2.1×100 mm, 1.7 μm particles; SolventA=0.1% Formic acid in 95:5 Water:MeCN; Solvent B=0.1% Formic Acid in5:95 Water:MeCN; Flow Rate=0.8 mL/min.; Start % B=0, Final % B=100;Gradient Time=3.5 min, then a 1 min hold at 100% B. Detection=220 and254 nm.

LCMS Method G:

Column=XBridge C18 2.1×50 mm, 3.5 μm particles; Solvent A=95:5Water:MeCN w/ 10 mM NH₄OAc; Solvent B=5:95 Water:MeCN 10 mM NH₄OAc; FlowRate=1.0 mL/min.; Start % B=0, Final % B=100; Gradient Time=3 min, thena 1 min hold at 100% B. Detection=220 nm and 254 nm.

LCMS Method H:

Column=Acquity CSH C18, 2.1×30 mm, 1.7 μm particles; Solvent A=0.1%Formic acid in 100% Water; Solvent B=0.1% Formic Acid in 100%Acetonitrile; Flow Rate=0.8 mL/min.; Start % B=5, Final % B=95; GradientTime=1.7 min, then a 0.2 min hold at 95% B. Detection=215 and 254 nm.

General HPLC Purification Conditions:

HPLC purification was performed using one of the conditions indicatedbelow, optionally followed by a second HPLC purification using adifferent condition indicated below. Based on analytical HPLC dataobtained on the crude reaction mixture, the purification condition wasoptimized for each target compound by modifying the initial SolventA:Solvent B ratio, the gradient time, the final Solvent A:Solvent Bratio, and the hold time at the final Solvent A:Solvent B concentration.

HPLC Condition A: Column: Zorbax Eclipse Plus C18, 21.2×100 mm, 5 μmparticles; Solvent A=0.1% Formic Acid in 100% Water. SolventB=Acetonitrile. Flow Rate=40 mL/min. Wavelength=215 and 254 nm.ESI+Range: 150 to 1500 dalton.

HPLC Condition B: Column: Sunfire prep C18 OBD, 30×100 mm, 5 μmparticles; Solvent A: water:MeCN 95:5 w/ 0.1% TFA, Solvent B: MeCN:water95:5 w/ 0.1% TFA. Flow Rate=42 mL/min. Wavelength=220 and 254 nm.

HPLC Condition C: Column: Waters Xterra C18, 19×100 mm, 10 μm particles;Solvent A=0.1% NH4OH in 100% Water. Solvent B=Acetonitrile. Flow Rate=40mL/min. Wavelength=215 and 254 nm. ESI+Range: 150 to 1500 dalton.

HPLC Condition D: Column: Waters XSelect CSH C18, 19×100 mm, 5 μmparticles; Solvent A=0.1% Formic Acid in 100% Water. SolventB=Acetonitrile. Flow Rate=40 mL/min. Wavelength=215 and 254 nm.ESI+Range: 150 to 1500 dalton.

Preparation of bicyclo[3.1.0]hexan-3-ol

To a stirred solution of cyclopent-3-enol (130 g, 1545 mmol) in DCM(1200 mL) under N₂ atmosphere at 0-5° C. was added dropwise a solutionof diethyl zinc in hexane (1.0 M, 3091 mL, 3091 mmol) over a period of 3h. To the solution at 0° C. was added dropwise a solution ofdiiodomethane (249 mL, 3091 mmol) in DCM (300 mL) over a period of 1 h.The reaction mixture was allowed to warm to 27° C. upon which formationof a white precipitation was observed. The mixture stirred for 16 h.Progress of the reaction was monitored by TLC (SiO₂, 20% EtOAc/pet,Rf=0.3, UV-inactive, PMA-active). The reaction mixture was quenched viathe careful addition of aq. saturated NH₄Cl solution (1.5 L). Themixture was filtered through pad of Celite. The aqueous layer wasextracted with DCM (2×1L). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and then concentrated under reduced pressureto afford crude bicyclo[3.1.0]hexan-3-ol as red liquid, 180 g. ¹H NMR(400 MHz, CDCl₃)δ=4.41-4.35 (m, 1H), 2.18-2.05 (m, 2H), 1.73 (d, J=13.9Hz, 2H), 1.35-1.25 (m, 2H), 1.21-1.14 (m, 1H), 0.57-0.43 (m, 2H). GCMS:m/z=98.1).

Preparation of bicyclo[3.1.0]hexan-3-one

To a stirred solution of bicyclo[3.1.0]hexan-3-ol (210 g, 2054 mmol) inDCM (5000 mL) under N₂ atmosphere at 0° C. was added portion-wiseDess-Martin periodinane (954 g, 225 mmol). The mixture was allowed towarm to 27° C. and was then stirred for 16 h. Progress of the reactionwas monitored by TLC (SiO₂, 20% Acetone/Hex, Rf=0.3, UV in-active,PMA-active). The reaction mixture was filtered through pad of Celite andthe filtrate was washed with aq. NaOH (1N, 8×1 L). The combined aqueousphases were extracted with DCM (5×1 L). The combined organic layers weredried over anhydrous Na₂SO₄, filtered, and then concentrated underreduced pressure (bath temperature: 20° C.) to afford crudebicyclo[3.1.0]hexan-3-one as brown liquid. The liquid was furtherpurified by downward distillation at 70° C. to affordbicyclo[3.1.0]hexan-3-one as a pale yellow viscous liquid, 125 g (62%).¹H NMR (400 MHz, CDCl₃)δ=2.61-2.54 (m, 2H), 2.17-2.12 (m, 2H), 1.54-1.46(m, 2H), 0.92-0.86 (m, 1H), −0.01-−0.08 (m, 1H); GCMS: M/Z=96.1.

Preparation of 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-3-one

To a stirred solution of bicyclo[3.1.0]hexan-3-one (125 g, 1274 mmol) inTHF (1500 mL) under N₂ atmosphere at −78° C. was added LDA (2.0 M inTHF, 0.701 L, 1402 mmol). The solution was stirred for 1 h at −78° C. Tothe solution was added slowly over 30 minutes a solution ofethyldifluoroacetate (174 g, 1402 mmol) in THF (300 mL) maintaining atemperature of −78° C. The reaction mixture was allowed to warm to 27°C. and was then stirred for 1 h. Progress of the reaction was monitoredby TLC (SiO₂, 20% Acetone/Hexane, Rf=0.3, UV-active). The reactionmixture was quenched via the addition of aq. HCl (1N, 2000 mL). Themixture was stirred for 30 min. and then was extracted with EtOAc(3×1000 mL). The combined organic layers were washed with brine (1000mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to afford2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-3-one as a pale yellow viscousliquid, 180 g (71%). ¹H NMR (400 MHz, CDCl₃)δ=6.18 (t, J=54.8 Hz, 1H),2.70-2.62 (m, 1H), 2.35 (d, J=19.4 Hz, 1H), 2.14 (br s, 1H), 1.26-1.21(m, 1H), 1.04-1.03 (m, 1H), 0.22-0.21 (m, 1H), LCMS: M/Z=173.17).

Preparation of ethyl2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate.

To a stirred solution of 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-3-one(180 g, 910 mmol) in ethanol (2 L) under N₂ atmosphere at 27° C. wasadded ethyl 2-hydrazinylacetate hydrochloride (422 g, 2729 mmol)followed by sulfuric acid (20 mL, 375 mmol). The mixture was stirred for30 min. and then was heated to 100° C. and stirred for 16 h. Progress ofthe reaction was monitored by TLC (SiO₂, 20% Acetone/Hexane, Rf=0.3,UV-active). The reaction mixture was concentrated under reducedpressure. The residue was dissolved in EtOAc (2000 mL) and was washedwith water (2×1 L), brine (1.0 L), dried over anhydrous Na₂SO₄,filtered, and then was concentrated under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(pet.:acetone 100:0→98:2) to afford ethyl2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetateas an off-white solid, 110 g (46%). ¹H NMR (400 MHz, DMSO-d₆) δ=6.86 (t,J=54.8 Hz, 1H), 4.93 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.88-2.79 (m, 1H),2.76-2.68 (m, 1H), 2.14-2.04 (m, 2H), 1.19 (t, J=7.2 Hz, 3H), 1.10-1.03(m, 1H), 0.14 (q, J=4.3 Hz, 1H).

Preparation of ethyl2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate.

To a stirred solution of ethyl2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(110 g, 422 mmol) and Celite (395 g) in cyclohexane (3.5 L) at 0° C. wasadded portionwise pyridinium dichromate (794 g, 2110 mmol). To themixture under nitrogen atmosphere was added dropwise tert-butylhydroperoxide (355 mL, 2130 mmol) over a period of 10 min. The reactionmixture was warmed to 27° C. and was then stirred at that temperaturefor 48 h. Progress of the reaction was monitored by TLC (SiO₂, 30%Acetone/pet, Rf=0.4, UV-active). The reaction mixture was filtered, andthe filter cake was extracted with EtOAc (1000 mL). The filtrate waswashed with saturated aq. Na₂S₂O₃ (2×500 mL); saturated aq. FeSO₄ (300mL); and then brine (500 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to obtain thecrude title compound (150 g).

Preparation of ethyl2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)acetate.

To a stirred solution of ethyl2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(75 g, 269 mmol) in DCM (1500 mL) at 27° C. under nitrogen atmospherewas added ethane-1,2-dithiol (43.0 mL, 511 mmol) followed by theaddition of boron trifluoride acetic acid (72.6 mL, 511 mmol). Thesolution was stirred for 16 h. Progress of the reaction was monitored byTLC (SiO₂, 20% Acetone/Pet, Rf=0.35, UV-active). After completion, thereaction mixture was cooled to 0° C. and quenched via the addition ofaq. saturated NaHCO₃ (500 mL). The mixture was extracted with DCM(2×1000 mL). The combined organics were washed with brine (1000 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to obtain a brown liquid. This material was subjected to silicagel column chromatography (Pet.:EtOAc 95:5→90:10) to afford ethyl2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)acetate as an off-white solid, 80 g(74%). ¹H-NMR (400 MHz, CDCl₃) δ=6.61 (t, J=55.2 Hz, 1H), 5.00-4.85 (m,2H), 4.29-4.19 (m, 2H), 3.55-3.46 (m, 4H), 2.63-2.53 (m, 1H), 2.49-2.38(m, 1H), 1.30-1.24 (m, 4H), 0.65-0.60 (m, 1H). LCMS M+H=346.9.

Preparation of ethyl2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate

To a stirred solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione(26.3 g, 92 mmol) in DCM (20 mL) at −70° C. under N₂ atmosphere wasadded HF-pyridine (2.460 g, 24.83 mmol). The solution was for 30 min. Tothe solution was added a solution of ethyl2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-1,3]dithiolane]-1(3bH)-yl)acetate(10 g, 25 mmol) in DCM (20 mL). The reaction mixture was allowed to warmto -40° C. and then was stirred at that temperature for 1 h. Progress ofthe reaction was monitored by TLC (SiO2, 30% EtOAc/Pet, Rf=0.3, UVin-active). The reaction mixture was quenched via the addition of aq.sat. NaHCO₃ (200 mL). The mixture was warmed to room temperature and wasthen extracted with EtOAc (2×100 mL). The combined organics were washedwith brine (50 mL); dried over anhydrous Na₂SO₄; filtered; and wereconcentrated under reduced pressure to afford a brown solid. Thismaterial was subjected to silica gel column chromatography (Pet.:EtOAc100:0→75-25) to afford ethyl2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetateas a pale yellow solid, 8.5 g (91%). ¹H NMR (400 MHz, CDCl₃) δ=6.62 (t,J=55.2 Hz, 1H), 4.82 (s, 2H), 4.30-4.18 (m, 2H), 2.51-2.37 (m, 2H),1.42-1.35 (m, 1H), 1.31-1.23 (m, 3H), 1.14-1.08 (m, 1H). LCMSM+H=293.07.

Preparation of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid

To a stirred solution of ethyl2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(15 g, 50 mmol) in THF (17 mL) and MeOH (66 mL) at 0° C. under N₂atmosphere was added a solution of LiOH (1.788 g, 74.7 mmol) in water(66 mL). The reaction mixture was allowed to warm to 27° C. and was thenstirred for 3 h at that temperature. Progress of the reaction wasmonitored by TLC (SiO₂, 5% MeOH/DCM, Rf=0.2, UV Active). Aftercompletion, the reaction mixture was concentrated under reducedpressure; diluted with water (50 mL); and washed with EtOAc (2×250 mL)to remove impurities. The aqueous layer was adjusted to pH 2-3 using aq.HCl (1M), then was extracted with EtOAc (3×1000 mL). The combinedorganics were dried over anhydrous Na₂SO₄; filtered; and concentratedunder reduced pressure to afford2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid as an off white solid, 14 g (98%). LCMS M+H=265.15.

Separation affording2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid and2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid

2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (5.5 g) was dissolved in isopropanol (20 mL). The solution wassubjected portion-wise to SFC chiral separation as follows:Instrument=Thar 80; column=Chiralpak IC 30×250 mm, 5 micron; solventA=super critical CO₂; solvent B=isopropanol with 0.5% isopropylamine(v/v); eluent composition=70% A:30% B; flow-rate=65 g/min;back-pressure=100 bar; temperature=30° C.; injection volume=2.5 mL;detection=220 nm.2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid was collected as peak eluting from 7.5 min. to 14 min;2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid was collected as a peak eluting from 2.7 min. to 5.8 min. For eachenantiomer, the resulting solution was concentrated under reducedpressure and the resulting solids were dissolved in EtOAc, then twicewashed with aq. citric acid (1M) followed by water followed by brine.The organic solution was dried over Na₂SO₄; filtered; then concentratedin vacuo to afford the separated enantiomer in 80-90% recovery.

Preparation ofN-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide.

Step 1: Preparation of 2,6-dichloro-3-nitrobenzaldehyde

To a solution of sulfuric acid (H₂SO₄) (5.63 L, 4.5 V) in a round-bottomflask at 0-5° C. was added 2,6-dichlorobenzaldehyde (1.25 kg, 7.10 mol,1.0 equiv.) in portions at below 15° C. The reaction mass was stirred at0-5° C. for 30 min. A solution of freshly prepared nitration mixture[Prepared from Conc. H₂SO₄ (0.425 L, 0.34 V) and 70% HNO₃ (0.85 kg,13.49 mol, 1.30 equiv.) at 0° C.] was added to the above reactionmixture at below 10° C. [Note: Reaction is slightly exothermic (3-6°C.); so that addition is preferred at lower temperature]. The reactionmixture was stirred at 5-10° C. for 2-3 h. After completion of thereaction (monitored by TLC), it was quenched with ice cold water (18.75L, 15 V) at below 25° C. Then the reaction mass was allowed warm to roomtemperature and stirred for 2 h. The solids were isolated by filtrationand then were washed with water (2.5 L, 2.0 V). Bulk residual water wasremoved from the solids by maintaining vacuum filtration for 60-90 min.The crude wet solid was initially dried under air atmosphere; then in ahot air oven at 50-55° C. for 10-12 h (until moisture content is notmore than 5.0%) to get the dried title product,2,6-dichloro-3-nitrobenzaldehyde (1.44 kg, 92% yield) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ10. 44 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.56(d, J=8.8 Hz, 1H).

Step 2: Preparation of 2,6-dichloro-3-nitrobenzonitrile

(Step-2a) To a solution of DMSO (5.9 L, 5.0 V)) in a round-bottom flaskwas added 2,6-dichloro-3-nitrobenzaldehyde (1.17 kg, 5.31 mol, 1.0equiv.) at room temperature. After being stirred for 30 min at roomtemperature, hydroxylamine hydrochloride (0.63 kg, 9.04 mol, 1.70equiv.) was added and the reaction mass was stirred at room temperaturefor 3 h. After completion of the reaction (monitored by TLC), thereaction mass was quenched by the addition of ice-cold water (18.0 L,15.0 V) added at a rate sufficient to maintain the temperature below 30°C. (Observation: Solids formed upon water addition). The reaction masswas stirred at room temperature for 60-90 min. The solids were isolatedby filtration; washed with water (2.5 L, 2.0 V); followed by washingwith a mixture of acetone and hexanes (6.0 L, 1:1 ratio). Bulk residualwater was removed from the solids by maintaining vacuum filtration for60-90 min. The wet solid was initially air dried and then finally driedin a hot air oven at 50-55° C. for 10-12 h (until moisture content wasnot more than 1.0%) to get the dried target product,2,6-dichloro-3-nitrobenzaldehyde oxime (1.22 kg, 92% yield) as anoff-white solid. The crude product (which contains 10-20% of2,6-dichloro-3-nitrobenzonitrile) was used directly in the next stepwithout further purification.

(Step-2b) To a stirred solution of the crude oxime (preparationdescribed above, 1.13 kg, 4.80 mol, 1.0 equiv.) in DCM (9.04 L, 8.0 V)at 0-5° C. was added triethylamine (“TEA”, 1.02 kg, 10.09 mol, 2.1equiv.). After being stirred for 5 min, methanesulfonyl chloride (0.60kg, 5.29 mol, 1.1 equiv.) was added (Observation: An exotherm is notedduring the addition) slowly at 15° C. Then the reaction mass was stirredat room temperature for 30-45 min. After completion of the reaction(progress of reaction was monitored by TLC; mobile phase: 20% ethylacetate in hexanes), the reaction mass was diluted with water (6.78 L,6.0 V); the organic layer was separated; and the aqueous layer wasextracted with DCM (3.4 L, 3.0 V). The combined organic layers werewashed with brine (5.65 L, 5.0 V); dried over Na₂SO₄; and concentratedunder vacuum. The resulting crude solids were triturated with hexanes(4.50 L, 4.0 V) at room temperature. The wet material was dried in a hotair oven at 50-55° C. for 5-6 h to get the dried product,2,6-dichloro-3-nitrobenzonitrile (0.95 kg, 91% yield) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ8.07 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz,1H).

Step 3: Preparation of 4-chloro-7-nitro-1H-indazol-3-amine

To a stirred solution of 2,6-dichloro-3-nitrobenzonitrile (750.0 g, 3.45mol, 1.0 equiv.) in ethanol (7.5 L, 10.0 V) at 15-20° C. was slowlyadded hydrazine hydrate (519.0 g, 10.36 mol, 3.0 equiv.) whilemaintaining the reaction mass below 25° C. (Observation: Addition isslightly exothermic and solid formation will begin upon addition). Thereaction mixture temperature was slowly raised to room temperature andthen the mixture was stirred for 3 h (Observation: the quantity ofsolids will increase during this time). After completion of the reaction(monitored by TLC), the mixture was diluted with water (7.5 L, 10.0 V)and further stirred for 1 h at room temperature. The solids wereisolated via filtration and then were washed with water (2.25 L, 3.0 V).The wet solid was washed with a 1:1 ratio mixture of acetone (1.875 L,2.5 V) and hexanes (1.875 L, 2.5 V). Bulk residual water was removedfrom the solids by maintaining vacuum filtration for 60-90 min. The wetsolid was finally dried in a hot air oven for 7-8 h at 50° C. (untilmoisture content reaches below 1.5%) to get the dried product,4-chloro-7-nitro-1H-indazol-3-amine (549.0 g, 75% yield) as a brickred-colored solid. ¹H NMR (400 MHz, CDCl₃): δ10.36 (bs, 1H), 8.20 (d,J=8.4 Hz, 1H), 7.07 (d, J=8.40 Hz, 1H), 4.73 (bs, 2H).

Step 4: Preparation of 4-chloro-1-methyl-7-nitro-1H-indazol-3-amine

To a stirred solution of 4-chloro-7-nitro-1H-indazol-3-amine (500 g,0.42 mol, 1.0 equiv.) in DMF (5.0 L, 10.0 V) at 5-10° C. was slowlyadded cesium carbonate (Cs₂CO₃) (1.91 kg, 5.88 mol, 2.5 equiv.) whilemaintaining the reaction mass below 10° C. After being stirred for 5-10min, dimethyl sulphate (326.3 g, 2.59 mol, 1.1 equiv.) was added whilemaintaining the reaction mass below 10° C. (Note: Slow addition ispreferred for obtaining more favorable regio-selectivity). Then, thereaction temperature was slowly raised to room temperature and stirringwas continued an additional 2 h at the same temperature. Aftercompletion of the reaction (monitored by TLC), the reaction mass wasquenched by the addition of ice-cold water (15.0 L, 30.0 V) and theresulting mixture was then stirred for 6-8 h at room temperature. Thesolids were isolated via filtration and were then washed with water (1.5L, 3.0 V). The wet solid was washed with IPA (1.5 L, 3.0 V) followed byhexanes (1.0 L, 2.0 V). Bulk residual water was removed from the solidsby maintaining vacuum filtration for 60-90 min. The wet solid was driedin a hot air oven for 7-8 h at 50° C. (until moisture content is below1.0%). The isolated material,4-chloro-1-methyl-7-nitro-1H-indazol-3-amine (319.0 g, 60% yield), wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃): δ7.97 (d, J=8.32 Hz, 1H), 6.97 (d, J=8.24 Hz, 1H), 4.63 (bs,2H), 3.96 (s, 3H).

Step 5: Preparation ofN-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)methanesulfonamide

(Step 5a) To a solution of 4-chloro-1-methyl-7-nitro-1H-indazol-3-amine(625.0 g, 2.76 mol, 1.0 equiv.) in DCM (6.25 L, 10.0 V) at 0-5° C. wasadded triethylamine (TEA) (837.0 g, 8.27 mol, 3.0 equiv.); followed bythe addition of 4-dimethylaminopyridine (DMAP) (20.60 g, 0.165 mol, 0.06equiv.). The reaction mass was stirred for 5-10 min., thenmethanesulfonyl chloride (MSCl) (790.0 g, 6.89 mol, 2.5 equiv.) addedslowly while maintaining the reaction mass below 10° C. The reactionmixture was allowed to warm to room temperature and was then stirred for1.5-2.0 h. After completion of the reaction (monitored by TLC), themixture was diluted with water (6.25 L, 10.0 V) and then stirred at roomtemperature for 15 min. The organic layer was separated, and the aqueouslayer was extracted with DCM (6.25 L, 10.0 V). The combined organiclayers were washed with brine (1.25 L, 2.0 V), dried over Na₂SO₄ andconcentrated to get the crude solids. The solids were triturated withhexanes (1.25 L, 2.0 V) at room temperature to obtain the intermediate,N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide,which was used directly in the next step.

(ii) To a stirred solution ofN-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(prepared above) in ethanol (10.5 L, 20.0 V) at room temperature wasadded slowly an aq. 5% NaOH solution (4.38 L, 7.0 V) [Note: Slowaddition is preferred via dropping funnel]. The reaction mass wasstirred at the same temperature for 3 h. After completion of thereaction (monitored by TLC) [Sample preparation for TLC analysis: ˜1.0ml of sample acidified with aq. 2.0 N HCl to reach the pH: 2-3, extractit with ethyl acetate and analyze the organic layer by TLC], thereaction mass was cooled to 0-5° C. and the pH was adjusted to 2-3 bythe addition of aq. 2.0 N HCl (3.13 L, 5.0 V) while maintain thereaction temperature below 10° C. [Note: Precipitation occurred uponaddition of HCl and increased with stirring]. The reaction mixture waswarmed to room temperature and then stirred for 1.5-2.0 h. Solidsobtained were isolated via filtration and were then washed with water(1.25 L, 2.0 V); followed by washing with hexanes (1.25 L, 2.0 V). Bulkresidual water was removed from the solids by maintaining vacuumfiltration for 60-90 min. The wet material was dried in a hot air ovenat 50° C. for 6-7 h (Until the moisture content is below 1.0%) to getthe dried product,N-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)methanesulfonamide (640.0g, 76%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ8.05 (d, J=8.32 Hz,1H), 7.32 (bs, 1H), 7.17 (d, J=8.28 Hz, 1H), 4.15 (s, 3H), 3.45 (s, 3H).

Step 6: Preparation ofN-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a mixture ofN-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)methanesulfonamide (635.0g, 2.08 mol, 1.0 equiv.) and 1-(chloromethyl)-4-methoxybenzene (359.0 g,2.30 mol, 1.1 equiv.) in DMF (6.35 L, 10.0 V) at room temperature wasadded potassium carbonate (374.7 g, 2.70 mol, 1.3 equiv.). The reactionmixture was heated to 80-90° C. and maintained at that temperature for 3h. After completion of the reaction (monitored by TLC), the mixture waspoured into ice cold water (19.05 L, 30.0 V) [Note: Slow quenching withvigorous stirring is preferred to avoid clumping as the productprecipitates]. The resulting solids were isolated via filtration andwashed with water (1.90 L, 3.0 V); then the solids were washed withhexanes (1.27 L, 2.0 V). Bulk residual water was removed from the solidsby maintaining vacuum filtration for 60-90 min. The isolated solid wasdissolved in Ethyl acetate (12.7 L, 20.0 V) and charcoal was added (63.5g). The mixture was heated to 60-70° C. and then stirred for 30-45 min.at that temperature. The mixture was filtered while still hot (40-50°C.) through a pad of Celite and the Celite pad was then extracted withethyl acetate (3.17 L, 5.0 V). The combined filtrates were concentratedto dryness under reduced pressure at below 50° C. Ethyl acetate (0.635L, 1.0 V) was added to the solids at room temperature. The resultantsolid suspension was stirred for 30 min. The solids were isolated viafiltration and then were washed with hexanes (1.27 L, 2.0 V). Residualwater was removed from the solids by maintaining vacuum filtration for45-60 min. to afford the productN-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methane sulfonamide (705.0 g, 80% yield) as a yellow solid. ¹H NMR (400MHz, CDCl₃): δ7.99 (d, J=8.24 Hz, 1H), 7.27 (d, J=8.68 Hz, 2H), 7.19 (d,J=8.24 Hz, 1H), 6.80 (d, J=8.44 Hz, 2H), 4.95-4.76 (m, 2H), 4.17 (s,3H), 3.76 (s, 3H), 3.01 (s, 3H).

Step 7: Preparation ofN-(7-Amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a stirred suspension of zinc powder (540.0 g, 8.23 mol, 10.0 equiv.)in a mixture of THF (3.50 L, 10.0 V) and water (7.0 L, 20.0 V) at roomtemperature was added ammonium chloride (NH₄Cl) (449.0 g, 8.23 mol, 10.0equiv.). To the mixture was addedN-(4-chloro-1-methyl-7-nitro-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide(350 g, 0.823 mol, 1.0 equiv.) in THF (7.0 L, 20.0 V). The reactionmixture was stirred at room temperature for 3-4 h. After completion ofthe reaction (monitored by in-process TLC/HPLC), the mixture was dilutedwith ethyl acetate (3.5 L, 10.0 V) and water (1.12 L, 2.5 V). Themixture was stirred for 15 min. The reaction mass was filtered through apad of Celite bed washing with ethyl acetate (1.75 L, 5.0 V). Thebi-phasic filtrate was collected, and the phases were separated. Theaqueous layer was extracted with ethyl acetate (3.50 L, 10.0 V). Thecombined organic layers were washed with brine (3.50 L, 10 V), driedover Na₂SO₄, and then concentrated in vacuo to afford a crude solid. Tothe crude product was added MTBE (3.25 L, 10 V) and the suspension wasstirred for 30 min at room temperature. The solids were isolated byfiltration. Bulk residual water was removed from the solids bymaintaining vacuum filtration for 30-45 min. The wet product was driedin a hot air oven (50° C.) for 2 h to afford the title product,N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide(276.0 g, 85% yield) as off-white solid. ¹H NMR (400 MHz, CDCl₃):δ7.29-7.26 (m, 2H), 6.86-6.79 (m, 2H), 6.42 (d, J=7.80 Hz, 1H),4.99-4.70 (m, 2H), 4.25 (s, 3H), 3.77 (s, 5H), 2.98 (s, 3H).

Preparation of 2-amino-6-(benzyloxy)nicotinic acid

A solution of 2-amino-6-chloronicotinic acid (5 g, 29 mmol) andpotassium tert -butoxide (9.75 g, 87 mmol) in benzyl alcohol (97 mL) wasstirred at 120° C. for 3 h. After cooling to ambient temperature, thevery dark reaction mixture was diluted with water and then washed withether (x3). The aqueous layer was then acidified with 0.5 M citric acid.The tan precipitate was isolated by filtration to provide the product(4.4 g, 62%) which was used in the next reaction without furtherpurification. ¹H NMR (500 MHz, DMSO-d6) δ12.40 (br s, 1H), 7.94 (d,J=8.55 Hz, 1H), 7.06-7.52 (m, 5H), 6.04 (d, J=8.24 Hz, 1H), 5.33 (s,2H). LC/MS: m/z=245.15 [M+1 ]⁺.

Preparation ofN-[(6P)-7-{2-[(1S)-1-amino-2-(3,5-difluorophenyl)ethyl]-7-hydroxy-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-3-yl}-4-chloro-1-methyl-1H-indazol-3-yl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide

Step 1:

To a suspension of(S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid(5.49 g, 18.23 mmol) and 2-amino-6-(benzyloxy)nicotinic acid (4.45 g,18.23 mmol) in acetonitrile (92 mL) (yellow solution) at −25° C. wasadded pyridine (9.83 mL, 122 mmol) followed by2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (“T3P”,45.2 ml, 76 mmol). The reaction mixture (became a clear solution afterT₃P addition) was stirred at −25° C. to 10° C. over 4.5 h, thenN-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide(6 g, 15.19 mmol) was added and the mixture was stirred for 18 h whilewarming to rt. The reaction mixture was diluted with ethyl acetate,washed with 1N NaOH, then water, then 0.5 M citric acid, then water,then dried over Na₂SO₄ and concentrated in vacuo. The resulting residuewas purified on silica (330 g RediSep Gold column) using 0-60% ethylacetate in hexanes over 15 CV, then holding at 60% EtOAc for 10 CV. Thedesired fractions were pooled and concentrated to afford a pale yellowsolid (8.1 g, 9.14 mmol, 60.1% yield), a mixture of tert-butylN-[(1S)-1-[(3P,3P)-7-(benzyloxy)-3-(4-chloro-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamido}-1-methyl-1H-indazol-7-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]carbamate(major) and tert-butylN-[(1S)-1-[(3M,3M)-7-(benzyloxy)-3-(4-chloro-3-{N-[(4-methoxyphenyl)methyl]methanesulfonamido}-1-methyl-1H-indazol-7-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]carbamate(minor). LC/MS: m/z=886.25[M+1]⁺.

Step 2:

TFA (21.1 mL, 274 mmol) was added to a solution of tert-butyl(S)-(1-(7-(benzyloxy)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(Product from Step 1, 8.1 g, 9.14 mmol) in dichloromethane (45.7 mL).The mixture was stirred at rt for 2 h. The resultant pale yellowsolution was concentrated. The residue was taken up in ethyl acetate,then washed three times with 1 N NaOH, then dried over Na2SO4 and thenconcentrated in vacuo to afford an oily residue. The residue waspurified on silica gel (330 g RediSep Gold column) by a gradient methodof Solvent A:Solvent B 65:35→0:100 (2 CV), then 0:100 (9 CV); SolventA=hexanes; Solvent B=9:9:2 hexanes:ethyl acetate:MeOH. The first elutingisomer (major) was collected and concentrated in vacuo to affordN-[(6P)-7-{2-[(1S)-1-amino-2-(3,5-difluorophenyl)ethyl]-7-hydroxy-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-3-yl}-4-chloro-1-methyl-1H-indazol-3-yl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide(4.1 g, 5.89 mmol, 64.5% yield). ¹H NMR (500 MHz, DMSO-d6) δ 7.86-7.98(m, 1H) 7.15-7.37 (m, 4H) 6.97-7.06 (m, 1H) 6.70-6.89 (m, 4H) 6.40-6.48(m, 1H) 4.70-4.88 (m, 2H) 3.41-3.81 (m, 7H) 3.20-3.28 (m, 1H) 3.08-3.12(m, 3H) 2.71-2.79 (m, 1H) 1.69-2.00 (m, 2H). LC/MS: m/z=696.20[M+1]⁺.

Preparation ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsuIfonamido)-1-methyl-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a stirred solution ofN-[(6P)-7-{2-[(1S)-1-amino-2-(3,5-difluorophenyl)ethyl]-7-hydroxy-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-3-yl}-4-chloro-1-methyl-1H-indazol-3-yl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide(0.926 g, 1.330 mmol) in DMF (13 ml) was added2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (0.351 g, 1.330 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (“HATU”, 0.531 g, 1.397 mmol), and DIPEA (0.581ml, 3.33 mmol). The reaction mixture was stirred for 2 h after which thereaction mixture was diluted with water and extracted with ethylacetate. The combined EtOAc extractions were washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The crude product was purifiedvia silica gel flash chromatography using 10-100% ethyl acetate inhexanes to provideN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.1 g, 88%) as an off-white foamy solid. LC/MS: m/z=942.25 [M+1]⁺.

Preparation ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a solution ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(0.05 g, 0.053 mmol) in DCM (1 mL) and TFA (0.250 mL) was added triflicacid (0.014 mL, 0.159 mmol). The resultant purple solution was stirredfor 1 h and then concentrated in vacuo. The crude residue was taken upin ethyl acetate and washed with saturated aqueous NaHCO3. The organiclayer was concentrated in vacuo and then purified HPLC to afford thetitle compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.¹H NMR (500 MHz, METHANOL-d4) δ 8.09-8.17 (m, 1H) 7.27-7.32 (m, 1H)7.16-7.21 (m, 1H) 6.58-6.85 (m, 5H) 4.81-4.83 (m, 2H) 4.42-4.47 (m, 2H)3.65-3.70 (m, 3H) 3.43-3.49 (m, 1H) 3.23-3.27 (m, 3H) 3.06-3.14 (m, 1H)2.41-2.50 (m, 2H) 1.35-1.41 (m, 1H) 0.96-1.02 (m, 1H). LCMS Method A:retention time=1.15 min; observed ion=822.6 [M+H]⁺

Preparation ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a stirred solution ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(2 g, 2.433 mmol) in N,N-Dimethylformamide (12 mL) were added Aceticacid (0.84 mL, 14.60 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (“HATU”, 1.295 g, 3.41 mmol) and DIPEA (1.3 mL,7.30 mmol). The reaction mixture was stirred for 2 days at rt. Themixture was diluted with ethyl acetate (200 mL), washed with water,brine, dried over Na₂SO₄, filtered, concentrated and the residue waspurified by silica gel chromatography (120 g RediSep Gold column) using10-80% ethyl acetate in hexanes over 15 CV, then at 80% ethyl acetate inhexanes for 10 CV. The desired fractions were pooled and thenconcentrated to afford N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.89 g, 90%) as a pale yellow solid. LC/MS: m/z=864.05[M+1]⁺.

Preparation ofN-((S)-1-((3P)-7-chloro-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

N-(1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(0.1 g, 0.106 mmol) in phosphorus oxychloride (0.53 mL) was heated at80° C. for 3 h and then was concentrated in vacuo. The residue was takenup in ethyl acetate, washed with sat. NaHCO₃, brine, dried over Na₂SO₄and concentrated under reduced pressure to give a yellow solid (used asis in the next step). LC/MS: m/z=960.15[M+1]⁺.

Preparation ofN-((S)-1-(7-chloro-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

A solution ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.0 g, 1.2 mmol) in POCl₃ (12 mL) was stirred overnight (app 18 h) at40° C. The solution was poured over of ice (100 g) and then was dilutedwith EtOAc and stirred until the mixture had reached room temperature.The organic phase was isolated and dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford an orange oil (˜15 g). The material wasadsorbed onto Celite and the resulting powder was subjected to silicagel purification (40 g, eluted with 30-100% ethyl acetate in hexanesover 5 CVs and then 100% ethyl acetate over 5 CVs). Fractions containingthe desired product were pooled and then concentrated in vacuo. TLCanalysis indicated that an impurity co-eluted with the desired product,suggesting that the quench of the POCl₃ had been incomplete. Theisolated material (˜13 g) was stirred with water and then was extractedwith ethyl acetate. The organic phase was washed with sat. aq. sodiumcarbonate upon which the organic phase turned from a colorless to ayellow solution and the aqueous phase tested as pH>7. The organic phasewas isolated and then concentrated in vacuo to affordN-((S)-1-(7-chloro-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(865 mg, 1.029 mmol, 85% yield). LCMS Method D: retention time=2.961min.; observed ion=841.95 (M+H). ¹H NMR (500 MHz, METHANOL-d₄) δ ppm0.99 (td, J=3.73, 2.09 Hzz, 1H) 1.34 (br dd, J=7.60, 1.94 Hz, 1H)2.37-2.46 (m, 2H) 3.04-3.13 (m, 5H) 3.43 (d, J=4.17 Hz, 1 H) 3.45-3.46(m, 1H) 3.53 (s, 3H) 4.90 (s, 1H) 6.54-6.79 (m, 4H) 7.16 (q, J=7.75 Hz,2 H) 7.69-7.72 (m, 1H) 8.63-8.66 (m, 1H). The LCMS and NMR dataindicated that the sample contained approximately about 20% mol ofN-((R)-1-(7-chloro-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(the diastereomer) that had formed in the reaction.

Preparation ofN-((S)-1-(7-bromo-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a solution ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.0 g, 1.2 mmol) in 1,2-Dichloroethane (DCE) (12 ml) was addedphosphoryl tribromide (1.7 g, 6.1 mmol) and the solution was thenstirred at 60° C. for 2 hrs. To the solution was added phosphoryltribromide (1.7 g, 6.1 mmol) the solution was stirred at 60° C. for 3hrs. The solution was cooled to room temperature and then was pouredover ice (100 g). The mixture was diluted with EtOAc and then stirreduntil the mixture warmed to room temperature (approximately 15 minutes).The organic phase was washed with sat. sodium carbonate until the pHwas >7 upon which the color of the organic phase changed from colorlessto yellow. The organic phase was concentrated in vacuo and adsorbed ontoCelite. The resulting powder was subjected to silica gel chromatography(40 g column, ethyl acetate and hexanes as eluent) to affordN-((S)-1-(7-bromo-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(932 mg, 1.05 mmol, 87% yield). LCMS Method D: retention time=2.987 min;observed ion=885.80 (M+H). ¹H NMR (500 MHz, METHANOL-d₄) δ ppm 0.99 (brd, J=2.98 Hz, 1H) 1.35 (s, 1H) 2.41 (br dd, J=6.56, 4.17 Hz, 2H)3.04-3.15 (m, 4H) 3.54 (s, 2H) 4.57 (d, J=14.60 Hz, 1H) 4.77 (s, 1H)4.79-4.83 (m, 2H) 6.41-6.84 (m, 4H) 7.12-7.21 (m, 2H) 7.85 (s, 1H) 7.86(t, J=3.98 Hz, 1H) 8.50-8.53 (m, 1H). The LCMS and NMR data indicatedthat the sample contained approximately about 30% mol ofN-((R)-1-(7-bromo-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(the diastereomer) that had formed in the reaction.

Preparation of(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate

To a solution ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(2.12 g, 2.58 mmol) and1,1,1-trifluoro-N-(pyridin-2-yl)-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.940 g, 5.42 mmol) in dichloromethane (12.9 mL) was addedtriethylamine (0.76 mL, 5.42 mmol) and the mixture was stirred at rt for18 h. The reaction mixture was then directly subjected to silica gelchromatography (120 g RediSep column) eluting with 0-60% ethyl acetatein hexanes over 10 CV, then at 60% ethyl acetate in hexanes for 8 CV.The desired fractions were pooled and then concentrated under reducedpressure to afford(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (1.6 g, 1.677 mmol, 65.0% yield) as anoff-white solid foam. LC/MS: m/z=955.95 [M+1]⁺.

Preparation of(3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate

To a solution ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.2 g, 1.273 mmol) and1,1,1-trifluoro-N-(pyridin-2-yl)-N-((trifluoromethyl)sulfonyl)methanesulfonamide(0.958 g, 2.67 mmol) in Dichloromethane (DCM) (10 mL) was addedtriethylamine (0.373 mL, 2.67 mmol) and the mixture was then stirred atrt for 18 h. The reaction mixture was loaded directly onto a silica gelcolumn (220 g RediSep) and purified using 0-80% ethyl acetate in hexanesas eluent. The desired fractions were concentrated to afford(3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (900 mg, 0.838 mmol, 65.8% yield). LCMS(M+H)+=1074.05

Preparation of(3P)-3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate

To a solution ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3.3 g, 3.82 mmol) and1,1,1-trifluoro-N-(pyridin-2-yl)-N-((trifluoromethyl)sulfonyl)methanesulfonamide(3.42 g, 9.55 mmol) in Dichloromethane (DCM) (20 mL) was addedtriethylamine (1.331 mL, 9.55 mmol) and the mixture was stirred at rtfor 18 h. The reaction mixture was then loaded directly on silica gelcolumn (330 g isco) and purified using 0-80% ethyl acetate in hexanesgradient. The desired fractions were pooled and then concentrated invacuo to afford(3P)-3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (2.5 g, 2.509 mmol, 65.7% yield) as anoff-white foamy solid. LCMS (M+H)=996.00

Preparation ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsuIfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

A 5 mL microwave vial was charged with 1,1,1,2,2,2-hexabutyldistannane(0.19 mL, 0.375 mmol),N-((S)-1-((3P)-7-chloro-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(0.3 g, 0.312 mmol) and Pd(PPh₃)₄ (0.036 g, 0.031 mmol). To the mixturewas added degassed (bubbled with Nitrogen for 2 minutes)N,N-Dimethylformamide (3.12 mL). The mixture was stirred and purged withnitrogen for 2 min. The vial was capped and heated at 110° C. for 18 h.The reaction mixture was diluted with ethyl acetate, washed with water,brine, dried over Na₂SO₄ and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (24 g RediSep Goldcolumn) using 0-60% ethyl acetate in hexanes over 20 CV. The desiredfractions were pooled and then concentrated under reduced pressure toaffordN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideas a clear oil (0.11 g, 0.093 mmol, 30% yield). LC/MS: m/z=1216.2[M+1]⁺.

Preparation ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

A 5 mL microwave vial was charged with 1,1,1,2,2,2-hexabutyldistannane(0.75 ml, 1.5 mmol),N-((S)-1-(7-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(500 mg, 0.595 mmol), Pd(PPh₃)₄ (69 mg, 0.059 mmol) andN,N-Dimethylformamide (DMF) (5.9 ml). The vial was capped and themixture was degassed (brief vacuum evacuation followed by refill withAr, repeated 3 times). The mixture was stirred under Ar atmosphere at100° C. overnight (app 18 hrs). The reaction mixture was diluted withethyl acetate, washed with water and then brine, dried over Na₂SO₄,filtered and then concentrated in vacuo. The resulting residue waspurified by silica gel chromatography (40 g RediSep Gold column) using0-100% ethyl acetate in hexanes over 10 CV and then 100% ethyl acetatefor 5 CVs. Fractions containing the desired product were pooled and thenconcentrated in vacuo to affordN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(45 mg, 0.041 mmol, 6.91% yield). LCMS Method D: retention time=4.166min; observed ion=1095.90 (M+H). ¹H NMR (500 MHz, METHANOL-d₄) δ ppm1.19-1.23 (m, 2H) 1.27-1.43 (m, 19H) 1.62-1.69 (m, 8H) 3.24 (s, 3H) 3.62(s, 2H) 4.54-4.58 (m, 8H) 6.52-6.82 (m, 4H) 7.19-7.33 (m, 2H) 7.84-7.87(m, 1H) 8.36-8.53 (m, 1H)

Alternate Preparation ofN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

A 5 mL microwave vial was charged with 1,1,1,2,2,2-hexabutyldistannane(1.0 mL, 2.0 mmol),N-((S)-1-(7-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(710 mg, 0.802 mmol), Pd(PPh₃)₄ (93 mg, 0.080 mmol) andN,N-Dimethylformamide (DMF) (8.0 mL). The vial was capped and themixture was degassed (brief vacuum evacuation followed by refill withargon, repeated 3 times). The mixture was stirred under argon atmosphereat 120° C. overnight (app 18 hrs). The mixture was concentrated in vacuoand the residue was adsorbed onto Celite. The resulting powder wassubjected to silica gel chromatography (0-100% ethyl acetate in hexanesover 10 CVs) to affordN-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(233 mg, 0.213 mmol, 26.5% yield). LCMS Method D: retention time=4.166min; observed ion=1096.10 (M+H).

Preparation of (S)-tert-butyl(1-(6-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

To a mixture of(S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid(11.45 g, 38.0 mmol) and 2-amino-5-bromonicotinic acid (9.07 g, 41.8mmol) in acetonitrile (200 mL) (a white slurry) was added pyridine (7.37ml, 91 mmol) followed by dropwise addition over 5 minutes of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% inEtOAc, 113 mL, 190 mmol) upon which the mixture slowly turned to a browncolor. The mixture was stirred at 40° C. for 4 h. To the mixture wasaddedN-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide(15 g, 38.0 mmol) and the mixture was stirred at 40° C. for 18 h. Themixture was cooled to room temperature and then was filtered. Thefiltrate was concentrated under reduced pressure and the residue wassubjected to silica gel chromatography (330 g RediSep column, 10-90%EtOAc in hexanes) to afford the product tert-butyl(S)-(1-(6-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(4.85 g, 5.65 mmol, 14.86% yield) as a light brown foam. LCMS Method D:retention time=3.35 min.; observed ion=802.0/803.9 (M−tBu+H); RT(min)=3.35.

Preparation of(S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-bromo-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide

To a stirred solution of tert-butyl(S)-(1-(6-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(4.85 g, 5.65 mmol) in Dichloromethane (DCM) (28.2 ml) was added TFA(8.70 ml, 113 mmol). The solution was stirred at RT for 1 hr. Thesolution was concentrated under reduced pressure. The dark yellow oilyresidue was dissolved in EtOAc (50 mL) and washed with 1M NaOH (20 mL).The organic layer was washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure to afford the crude residue whichwas purified by silica gel chromatography (330 g RediSep Gold column,20-100% Solvent B in hexanes, Solvent B=9:18:3 Hexane:EtOAc:MeOH). Thispurification afforded two peaks containing the product mass(atropisomers). Fractions of the first peak to elute were pooled andconcentrated in vacuo to afford the product(S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-bromo-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide(2.58 g, 3.40 mmol, 60.2% yield) as a white foam. LCMS Method D:retention time=2.34 min.; observed ion=757.95/759.65 (M+H).

Preparation of N-((S)-1-((3P)-6-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a stirred solution of(S)-N-((6P)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-bromo-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide(2.58 g, 3.40 mmol),2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (0.988 g, 3.74 mmol), and HATU (1.551 g, 4.08 mmol) inTetrahydrofuran (THF) (34.0 mL) was added diisopropylethylamine (1.781mL, 10.20 mmol). The resulting mixture was stirred at RT for 2 hrs. Themixture was then concentrated in vacuo and the residue was dissolved inEtOAc (100 mL). The organic solution was washed with aq. 1 M HCl (100mL), then water (100 mL), then brine. The organic solution was dried(MgSO₄), filtered and then concentrated in vacuo to affordN-((S)-1-((3P)-6-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3.42 g, 3.40 mmol, 100% yield) as a light brown solid. LCMS Method D:retention time=3.29 min.; observed ion=1004.0/1005.9 (M+H).

Preparation ofN-((S)-1-((3P)-6-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a stirred solution ofN-((S)-1-((3P)-6-bromo-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(3.42 g, 3.40 mmol) in Dichloromethane (DCM) (17.01 ml) was added TFA(7.86 ml, 102 mmol) followed by triflic acid (0.906 ml, 10.21 mmol). Thesolution was stirred at RT for 1 hr. The solution was concentrated underreduced pressure. The dark red oily residue was dissolved in EtOAc (75mL) and washed with 1M NaOH (60 mL). The organic layer was washed withbrine, dried (MgSO₄), filtered and concentrated under reduced pressureto afford the crude residue which was purified by silica gelchromatography (120 g RediSep Gold column, 10-75% EtOAc in hexanes) toafford the productN-((S)-1-((3P)-6-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(2.76 g, 3.12 mmol, 92% yield) as a white solid. LCMS Method D:retention time=2.95 min.; observed ion=884.0/885.9 (M+H).

Preparation ofN-((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a mixture ofN-((S)-1-((3P)-6-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.0 g, 1.130 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.301 g,1.186 mmol), PdCl₂(dppf) (0.041 g, 0.056 mmol), and potassium acetate(0.333 g, 3.39 mmol) was added degassed (bubbled with nitrogen for 5min.) 1,4-Dioxane (11.30 mL). The mixture stirred under nitrogenatmosphere at 80° C. for 2 hrs. The mixture was cooled to ambienttemperature and then was diluted with EtOAc. The organic solution waswashed with water, the brine, dried (MgSO₄), filtered and concentratedunder reduced pressure to afford the product N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(1.05 g, 1.13 mmol, 100% yield). LCMS Method D: retention time=2.59 min;observed ion=850.0 (M+H).

Preparation ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsuIfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a solution of(3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (400 mg, 0.372 mmol), (1H-pyrazol-3-yl)boronicacid (125 mg, 1.117 mmol) and K₃PO₄ (237 mg, 1.117 mmol) inTetrahydrofuran (THF) (4 mL)/Water (1.0 mL) was addedDichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(28.1 mg, 0.037 mmol) and the resulting mixture was heated at 50° C. for2 h. LCMS at this point indicated the desired product as a major peak.The mixture was cooled to room temp, diluted with ethyl acetate andwashed with water. The organic solution was dried (Na₂SO₄), filtered andconcentrated. The resulting residue was purified by silica gelchromatography (5-100% EtOAC in hexanes) to affordN-((S)-1-((3P-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(290 mg, 0.292 mmol, 78% yield). LCMS (M+H)+=992.10

Preparation ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a solution of(3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (120 mg, 0.112 mmol),(5-(trifluoromethyl)-1H-pyrazol-3-yl)boronic acid (60.3 mg, 0.335 mmol)and K₃PO₄ (71.1 mg, 0.335 mmol) in Tetrahydrofuran (THF) (2 mL)/Water(0.500 mL) was addedDichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(8.44 mg, 0.011 mmol) and the resulting mixture was heated at 50° C. for2 h. LCMS at this point indicated the desired product as the major peak.The mixture was then cooled to room temp, diluted with ethyl acetate andwashed with water. The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was then purified by silicagel chromatography (5-100% EtOAC in hexanes) to affordN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.LCMS (M+H)+=1060.10

Preparation ofN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a solution of(3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (120 mg, 0.112 mmol),(5-methyl-1H-pyrazol-3-yl)boronic acid (42.2 mg, 0.335 mmol) and K₃PO₄(71.1 mg, 0.335 mmol) in Tetrahydrofuran (THF) (2 mL)/Water (0.500 mL)was addeddichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(8.44 mg, 0.011 mmol) and the resulting mixture was heated at 50° C. for2 h. LCMS at this point indicated the desired product was the majorpeak. The mixture was then cooled to room temp, diluted with ethylacetate and washed with water. The organic phase was dried (Na₂SO₄),filtered and concentrated. The resulting residue was then purified bysilica gel chromatography (5-100% EtOAC in hexanes) to affordN-((S)-1-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(90 mg, 0.089 mmol, 80% yield). LCMS (M+H)+=1006.0

Preparation of Example 1:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-6-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a 1 dram vial charged withN-((S)-1-(6-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(35 mg, 0.040 mmol),2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine(21.60 mg, 0.079 mmol),Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II)(2.99 mg, 3.95 μmol) and K₃PO₄ (25.2 mg, 0.119 mmol) was added degassed(Nitrogen bubbling for 1 min) Tetrahydrofuran (THF) (1 mL):Water (0.25mL) and the resulting mixture was stirred at room temp for 16 h under anatmosphere of nitrogen. The LCMS indicated the reaction was complete.The reaction mass was transferred to a 20 mL scintillation vial. To themixture was added EtOAc (5 mL) and aqueous 1 M HCl (5 mL). The vial wassealed and shaken. The organic layer was pipetted away and concentratedin vacuo. The resulting residue was dissolved in DMF (2 mL) and was thensubjected to HPLC purification to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-6-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.46 min.;observed ion=951.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.86 (d,J=2.38 Hz, 1H), 9.40 (d, J=2.38 Hz, 1H), 8.46 (d, J=7.75 Hz, 1H), 8.24(t, J=7.75 Hz, 1H), 7.91 (d, J=7.75 Hz, 1H), 7.30-7.37 (m, 2H),6.57-6.84 (m, 4H), 4.57 (d, J=3.58 Hz, 2H), 3.68 (s, 3H), 3.53 (dd,J=14.01, 4.47 Hz, 1H), 3.26 (s, 3 H), 3.17 (dd, J=14.16, 9.69 Hz, 1H),2.39-2.47 (m, 2H), 1.33-1.39 (m, 1H), 1.01 (dtd, J=5.66, 3.80, 3.80,2.24 Hz, 1H)

Preparation of Example 2:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a 7 mL vial was charged withN-((S)-1-(6-bromo-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(45mg, 0.051 mmol), 4-(difluoromethyl)-2-(tributylstannyl)pyrimidine(32.0 mg, 0.076 mmol) ,copper(I) iodide (0.968 mg, 5.08 μmol) andPd(PPh₃)₄ (5.88 mg, 5.08 μmol) was added degassed (bubbled with Nitrogenfor 2 minutes) N,N-Dimethylformamide (DMF) (0.5 mL). The mixture wasstirred and purged with nitrogen for 2 min. The vial was capped and thenheated at 100° C. for 18 h. The LCMS indicated the reaction wascomplete. The reaction mixture was diluted with DMF (1.5 mL) and theresulting solution was subjected to HPLC purification to afford thetitle compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.4 min.;observed ion=934.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 10.11 (d,J=2.38 Hz, 1H), 9.68 (d, J=2.38 Hz, 1H), 9.20 (d, J=5.07 Hz, 1H), 7.79(d, J=5.07 Hz, 1H), 7.35 (d, J=2.09 Hz, 2H), 6.55-7.02 (m, 5H), 4.57 (d,J=4.47 Hz, 2H), 3.68 (s, 3H), 3.50-3.56 (m, 1H), 3.26 (s, 3H), 3.15-3.20(m, 1H), 2.40 -2.46 (m, 2H), 1.34-1.39 (m, 1H), 0.98-1.03 (m, 1H)

Preparation of Example 3:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(6-(difluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a 7 mL vial charged withN-((S)-1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(105 mg, 0.113 mmol), 2-chloro-6-(difluoromethyl)pyridine (20.27 mg,0.124 mmol), SPhos-Pd-G3 (8.79 mg, 0.011 mmol) and K₃PO₄ (71.7 mg, 0.338mmol) was added degassed (Nitrogen bubbling for 1 min) 1,4-Dioxane (845μl):Water (282 μl) and the resulting mixture was stirred at 60° C. for 1h under an atmosphere of nitrogen. The LCMS indicated the reaction wascomplete. The reaction mass was transferred to a 20 mL scintillationvial. To the mixture was added EtOAc (5 mL) and aqueous 1 M HCl (5 mL).The vial was sealed and shaken. The organic layer was pipetted away andconcentrated in vacuo. The residue was dissolved in DMF (2 mL) andsubjected to HPLC purification to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-(6-(difluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.42 min.;observed ion=933 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.73 (d,J=2.68 Hz, 1H), 9.26 (d, J=2.38 Hzz, 1H), 8.22 (dd, J=8.05, 0.89 Hz,1H), 8.06 (t, J=7.90 Hz, 1H), 7.67 (d, J=8.05 Hz, 1H), 7.22 (q, J=8.05Hz, 2H), 6.45-6.88 (m, 5H), 4.45 (d, J=3.28 Hz, 2H), 3.56 (s, 3H), 3.41(dd, J=14.16, 4.62 Hz, 1H), 3.14 (s, 3H), 3.02-3.09 (m, 1H), 2.28-2.34(m, 2H), 1.23-1.27 (m, 1H), 0.86-0.92 (m, 1H)

Preparation of Example 4:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(2-(trifluoromethyl)thiazol-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a 1 dram vial charged withN-((S)-1-(7-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(35 mg, 0.042 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)thiazole(23.24 mg, 0.083 mmol), SPhos-Pd-G3 (3.25 mg, 4.16 μmol) and K3PO4 (26.5mg, 0.125 mmol) was added degassed (nitrogen bubbling for 1 min)1,4-Dioxane (666 μl):Water (167 μl) and the resulting mixture wasstirred at 60° C. for 48 h under an atmosphere of nitrogen. The LCMSshowed a product peak but the reaction did not go to completion. Thereaction mixture was cooled to ambient temp, transferred to a 20 mLscintillation vial, and was diluted with EtOAc (5 mL) and aq. HCl (1 M,5 mL). The biphasic mixture was shaken. The organic layer was pipettedout and concentrated under reduced pressure. The residue was dissolvedin DMF (2 mL) and subjected to HPLC purification to afford the titlecompound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(2-(trifluoromethyl)thiazol-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.52 min.;observed ion=957.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.94 (s, 1H), 8.84 (d, J=8.35 Hz, 1H), 8.49 (d, J=8.05 Hz, 1H), 7.27-7.34 (m, 2H),6.57-6.83 (m, 4 H), 4.92-4.94 (m, 1H), 4.56 (d, J=4.47Hz, 2H), 3.67 (s,3H), 3.54 (dd, J=14.31, 4.77 Hz, 1H), 3.25 (s, 3H), 3.16-3.21 (m, 1H),2.43 (ddd, J=11.40, 7.53, 4.32 Hz, 2H), 1.35-1.39 (m, 1H), 0.99-1.02 (m,1H)

Preparation of Example 5:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using2-(tributylstannyl)-4-(trifluoromethyl)pyrimidine as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)pyrimidin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method A: retention time=1.45 min.;observed ion=952.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.38-9.45(m, 1H) 8.89-8.96 (m, 1H) 8.79-8.85 (m, 1H) 8.01 -8.09 (m, 1H) 7.22-7.34(m, 2H) 6.54-6.81 (m, 4H) 4.89-4.92 (m, 1H) 4.52-4.65 (m, 2 H) 3.61-3.68(m, 3H) 3.47-3.53 (m, 1H) 3.20-3.24 (m, 3H) 3.13-3.19 (m, 1H) 2.35 -2.45(m, 2H) 1.30-1.37 (m, 1H) 0.95-1.01 (m, 1H)

Preparation of Example 6:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using4-(difluoromethyl) -2-(tributylstannyl)pyrimidine as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(difluoromethyl)pyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method A: retention time=1.37 min.;observed ion=934.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.29-9.36(m, 1H) 8.88-8.93 (m, 1H) 8.80-8.85 (m, 1H) 7.89 -7.95 (m, 1H) 7.21-7.34(m, 2H) 6.56-7.05 (m, 5H) 4.89-4.93 (m, 1H) 4.54-4.62 (m, 2 H) 3.61-3.65(m, 3H) 3.47-3.54 (m, 1H) 3.22-3.24 (m, 3H) 3.13-3.19 (m, 1H) 2.36 -2.44(m, 2H) 1.30-1.37 (m, 1H) 0.96-1.01 (m, 1H)

Preparation of Example 7:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using2-methyl-3-(tributylstannyl)pyrazine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method A: retention time=1.34 min.;observed ion=898.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.80-8.89(m, 1H) 8.62-8.69 (m, 2H) 8.19-8.26 (m, 1H) 7.23 -7.35 (m, 2H) 6.55-7.09(m, 5H) 4.88-4.91 (m, 1H) 4.54-4.58 (m, 2H) 3.62-3.67 (m, 3 H) 3.47-3.52(m, 1H) 3.23-3.25 (m, 3H) 2.89-2.92 (m, 3H) 2.38-2.43 (m, 2H) 1.31 -1.37(m, 1H) 0.95-1.01 (m, 1H)

Preparation of Example 8:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrazin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using2-(tributylstannyl)pyrazine as the coupling partner. The experimentafforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrazin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method A: retention time=1.35 min.;observed ion=884.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.74 -9.86(m, 1H) 8.66-8.89 (m, 4H) 7.25-7.34 (m, 2H) 6.52-6.82 (m, 4H) 4.52-4.63(m, 3 H) 3.62-3.68 (m, 3H) 3.47-3.55 (m, 1H) 3.22-3.24 (m, 3H) 3.14-3.20(m, 1H) 2.37 -2.44 (m, 2H) 1.30-1.37 (m, 1H) 0.96-1.01 (m, 1H)

Preparation of Example 9:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using2-(tributylstannyl)-6-(trifluoromethyl)pyridine as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.52 min.;observed ion=951 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.91-8.94(m, 1H) 8.85-8.89 (m, 1H) 8.75-8.81 (m, 1H) 8.29-8.36 (m, 1H) 7.98-8.02(m, 1H) 7.29-7.37 (m, 2H) 6.56-6.84 (m, 4H) 4.90-4.95 (m, 1 H) 4.53-4.64(m, 2H) 3.66-3.69 (m, 3H) 3.50-3.57 (m, 1H) 3.26-3.27 (m, 3H) 3.18 -3.23(m, 1H) 2.37-2.48 (m, 2H) 1.34-1.40 (m, 1H) 0.97-1.05 (m, 1H)

Preparation of Example 10:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methylpyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using4-methyl-2-(tributylstannyl)pyrimidine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methylpyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.33 min.;observed ion=898.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.92-8.95(m, 1H) 8.87-8.90 (m, 1H) 8.78-8.81 (m, 1H) 7.54 -7.56 (m, 1H) 7.32-7.34(m, 1H) 7.23-7.26 (m, 1H) 6.58-6.83 (m, 4H) 4.91-4.96 (m, 1 H) 4.55-4.65(m, 2H) 3.63-3.68 (m, 3H) 3.49-3.56 (m, 1H) 3.26-3.28 (m, 3H) 3.14 -3.19(m, 1H) 2.73-2.77 (m, 3H) 2.39-2.46 (m, 2H) 1.34-1.39 (m, 1H) 0.99-1.04(m, 1 H)

Preparation of Example 11:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4,6-dimethylpyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure B using4,6-dimethyl-2-(tributylstannyl)pyrimidine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4,6-dimethylpyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.38 min.;observed ion=912.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.84-8.89(m, 1H) 8.72-8.77 (m, 1H) 7.41-7.44 (m, 1H) 7.31 -7.35 (m, 1H) 7.21-7.27(m, 1H) 6.57-6.83 (m, 4H) 4.91-4.96 (m, 1H) 4.55-4.63 (m, 2 H) 3.63-3.69(m, 3H) 3.49-3.57 (m, 1H) 3.24-3.27 (m, 3H) 3.15-3.21 (m, 1H) 2.66 -2.71(m, 6H) 2.38-2.46 (m, 2H) 1.33-1.39 (m, 1H) 0.98-1.04 (m, 1H)

Preparation of Example 12:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-(1,1-difluoroethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a 5 mL microwave vial charged withN-((S)-1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(tributylstannyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(0.113 g, 0.093 mmol), 2-bromo-6-(1,1-difluoroethyl)pyridine (0.062 g,0.279 mmol), copper(I) iodide (1.771 mg, 9.30 μmol) and Pd(PPh₃)₄ (10.74mg, 9.30 μmol) was added degassed (bubbled with nitrogen for 2 minutes)N,N-Dimethylformamide (1 mL). The mixture was stirred and purged withnitrogen for 2 min. The vial was capped and the mixture was heated at100° C. for 18 h. The reaction was diluted with water and extracted withEtOAc. The organic phase was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (12 g RediSep Gold column) using 0-70% ethyl acetate inhexanes over 10 CV, then 70% ethyl acetate in hexanes over 5 CV. Thedesired fractions were pooled and then concentrated to afford a yellowsolid. The solid was dissolved up in DCM (1 mL) and TFA (0.5 mL), and tothe solution was added triflic acid (0.025 ml, 0.279 mmol). Theresulting purple solution was stirred for 30 min and then wasconcentrated in vacuo. The residue was taken up in ethyl acetate and thepH was adjusted to pH>7 using aq. 1 N NaOH. The mixture was dried overNa₂SO₄ and then concentrated in vacuo. The resulting residue wasdissolved in DMF, the solution was filtered, and the filtrate wassubjected to prep-HPLC purification to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-(1,1-difluoroethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.53 min.;observed ion=947.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.23-8.29(m, 1H) 7.41-7.46 (m, 1H) 7.30-7.36 (m, 1H) 7.24 -7.28 (m, 1H) 7.10-7.16(m, 1H) 6.66-6.81 (m, 3H) 5.93-5.97 (m, 1H) 4.92-4.99 (m, 1 H) 4.30-4.39(m, 1H) 3.69-3.79 (m, 2H) 3.41-3.45 (m, 1H) 3.34-3.36 (m, 3H) 3.30 -3.30(m, 3H) 3.13-3.19 (m, 1H) 2.75-2.81 (m, 2H) 1.83-1.94 (m, 1H) 1.66-1.80(m, 1 H) 1.48-1.62 (m, 1H) 0.96-1.06 (m, 1H) 0.60-0.70 (m, 2H)

Preparation of Example 13:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyrazin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure F using2-chloro-6-(trifluoromethyl)pyrazine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyrazin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.5 min.;observed ion=952.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.92-9.99(m, 1H) 9.11-9.16 (m, 1H) 8.75-8.82 (m, 1H) 8.58 -8.65 (m, 1H) 7.19-7.27(m, 2H) 6.43-6.74 (m, 4H) 4.81-4.83 (m, 1H) 4.41-4.53 (m, 2 H) 3.54-3.58(m, 3H) 3.40-3.45 (m, 1H) 3.14-3.16 (m, 3H) 3.06-3.11 (m, 1H) 2.27 -2.34(m, 2H) 1.23-1.27 (m, 1H) 0.87-0.92 (m, 1H).

Preparation of Example 14:N-((S)-1-(7-(4,6-bis(trifluoromethyl)pyridin-2-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure F using2-chloro-4,6- bis(trifluoromethyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-(7-(4,6-bis(trifluoromethyl)pyridin-2-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.65 min.;observed ion=1019.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.20-9.27(m, 1H) 8.90-8.95 (m, 1H) 8.77-8.84 (m, 1H) 8.31-8.37 (m, 1H) 7.31-7.38(m, 2H) 6.55-6.84 (m, 4H) 4.92 (br d, J=4.47 Hz, 1H) 4.53-4.66 (m, 2H)3.66-3.70 (m, 3H) 3.51-3.57 (m, 1H) 3.27 (s, 3H) 3.18-3.23 (m, 1 H)2.39-2.46 (m, 2H) 1.34-1.39 (m, 1H) 0.99-1.04 (m, 1H)

Preparation of Example 15:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure F using4-chloro-6-(trifluoromethyl)pyrimidine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.52 min.;observed ion=952.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.59-9.65(m, 1H) 9.00-9.06 (m, 1H) 8.92-8.97 (m, 1H) 8.85 -8.89 (m, 1H) 7.32-7.41(m, 2H) 6.56-6.85 (m, 4H) 4.92-4.94 (m, 1H) 4.53-4.66 (m, 2 H) 3.65-3.72(m, 3H) 3.50-3.57 (m, 1H) 3.27 (br s, 3H) 3.17-3.21 (m, 1H) 2.39-2.46(m, 2H) 1.34-1.39 (m, 1H) 0.98-1.03 (m, 1H)

Preparation of Example 16:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure F using2-chloro-4-(trifluoromethyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsuIfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.53 min.;observed ion=951.3 (M+H). H NMR (500 MHz, METHANOL-d4) δ ppm 9.05-9.08(m, 1H) 8.98 (s, 1H) 8.86-8.89 (m, 1H) 8.79-8.82 (m, 1H) 7.86-7.91 (m,1H) 7.32-7.38 (m, 2H) 6.56-6.84 (m, 4H) 4.93-4.94 (m, 1H) 4.55 -4.68 (m,2H) 3.67-3.70 (m, 3H) 3.52-3.56 (m, 1H) 3.26-3.27 (m, 3H) 3.17-3.21 (m,1 H) 2.38-2.47 (m, 2H) 1.35-1.39 (m, 1H) 0.98-1.04 (m, 1H)

Preparation of Example 17:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure F using4-chloro-5-(trifluoromethyl)pyrimidine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.4 min.;observed ion=952.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.88-9.09(m, 3H) 8.07-8.13 (m, 1H) 7.31-7.38 (m, 2H) 6.54 -6.82 (m, 4H) 4.93-4.94(m, 1H) 4.49-4.60 (m, 2H) 3.68-3.72 (m, 3H) 3.49-3.55 (m, 1 H) 3.26-3.28(m, 3H) 3.12-3.17 (m, 1H) 2.37-2.47 (m, 2H) 1.34-1.40 (m, 1H) 0.97 -1.03(m, 1H)

Preparation of Example 18:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure F using4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.51 min.;observed ion=did not ionize ( ). 1H NMR (500 MHz, METHANOL-d4) δ ppm8.89-8.98 (m, 1H) 8.71-8.82 (m, 2H) 7.30-7.39 (m, 2H) 6.55-6.84 (m, 4H)4.92-4.93 (m, 1H) 4.52-4.61 (m, 2H) 3.66-3.70 (m, 3H) 3.55 (dd, J=14.46,4.32 Hz, 1H) 3.27 (s, 3H) 3.18-3.21 (m, 1H) 2.81-2.85 (m, 3H) 2.39-2.46(m, 2H) 1.34-1.39 (m, 1H) 0.99-1.04 (m, 1H)

Preparation of Example 19:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(4-fluoro-3-(trifluoromethyl)phenyl)boronic acid as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsuIfonamido)-1H-indazol-7-yl)-7-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method A: retention time=1.61 min.;observed ion=968.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.66-8.76(m, 1H) 8.28-8.39 (m, 2H) 8.11-8.19 (m, 1H) 7.77 -7.88 (m, 2H) 7.13-7.27(m, 2H) 6.41-6.74 (m, 4H) 4.40-4.52 (m, 2H) 3.53-3.58 (m, 3 H) 3.38-3.43(m, 1H) 3.14-3.15 (m, 3H) 3.03-3.09 (m, 1H) 2.26-2.34 (m, 2H) 1.21 -1.27(m, 1H) 0.86-0.91 (m, 1H)

Preparation of Example 20:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-(difluoromethoxy)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(3-(difluoromethoxy)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-(difluoromethoxy)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.52 min.;observed ion=948.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.78 (d,J=8.35 Hz, 1H) 8.20-8.27 (m, 1H) 8.10-8.17 (m, 2H) 7.62-7.70 (m, 1H)7.38-7.43 (m, 1H) 7.28-7.37 (m, 2H) 6.54-7.17 (m, 5H) 4.54-4.67 (m, 2H)3.63-3.69 (m, 3H) 3.49-3.56 (m, 1H) 3.25-3.27 (m, 3H) 3.15-3.21 (m, 1H)2.38-2.46 (m, 2H) 1.33-1.39 (m, 1H) 0.98-1.06 (m, 1H) 0.51-0.58 (m, 1H).

Preparation of Example 21:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(3-(trifluoromethoxy)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.6 min.;observed ion=966.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.77-8.85(m, 1H) 8.22-8.32 (m, 3H) 7.70-7.78 (m, 1H) 7.51 -7.58 (m, 1H) 7.26-7.38(m, 2H) 6.52-6.85 (m, 4H) 4.61 (d, J=14.60 Hz, 2H) 3.61-3.70 (m, 3H)3.52 (dd, J=14.16, 4.62 Hz, 1H) 3.26 (s, 3H) 3.19-3.23 (m, 1H) 2.38-2.48(m, 2 H) 1.33-1.40 (m, 1H) 0.98-1.05 (m, 1H)

Preparation of Example 22:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(4-fluoro-2-(trifluoromethyl)phenyl)boronic acid as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsuIfonamido)-1H-indazol-7-yl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.51 min.;observed ion=968.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.65-8.75(m, 1H) 7.49-7.72 (m, 4H) 7.20-7.27 (m, 2H) 6.43 -6.71 (m, 4H) 4.41-4.53(m, 2H) 3.56-3.59 (m, 3H) 3.35-3.41 (m, 1H) 3.15-3.17 (m, 3 H) 2.99-3.05(m, 1H) 2.27-2.33 (m, 2H) 1.23-1.27 (m, 1H) 0.86-0.91 (m, 1H)

Preparation of Example 23:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(3-(difluoromethyl)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-(difluoromethyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.51 min.;observed ion=932.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.74-8.86(m, 1H) 8.48-8.55 (m, 1H) 8.39-8.46 (m, 1H) 8.22 -8.31 (m, 1H) 7.73-7.84(m, 2H) 7.26-7.38 (m, 2H) 6.53-7.10 (m, 5H) 4.52-4.68 (m, 2 H) 3.65-3.69(m, 3H) 3.50-3.55 (m, 1H) 3.25-3.27 (m, 3H) 3.18-3.21 (m, 1H) 2.39 -2.46(m, 2H) 1.34-1.39 (m, 1H) 0.98-1.05 (m, 1H)

Preparation of Example 24:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(3-(trifluoromethyl)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.58 min.;observed ion=950.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.76-8.85(m, 1H) 8.65-8.70 (m, 1H) 8.49-8.56 (m, 1H) 8.27 -8.34 (m, 1H) 7.90-7.95(m, 1H) 7.81-7.88 (m, 1H) 7.29-7.38 (m, 2H) 6.55-6.84 (m, 4 H) 4.54-4.67(m, 2H) 3.64-3.69 (m, 3H) 3.49-3.57 (m, 1H) 3.26-3.28 (m, 3H) 3.15 -3.20(m, 1H) 2.39-2.47 (m, 2H) 1.34-1.39 (m, 1H) 0.98-1.05 (m, 1H).

Preparation of Example 25:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(2-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(2-(trifluoromethyl)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(2-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.49 min.;observed ion=950.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.75-8.87(m, 1H) 7.93-7.99 (m, 1H) 7.84-7.90 (m, 1H) 7.76 -7.83 (m, 2H) 7.66-7.71(m, 1H) 7.32-7.38 (m, 2H) 6.55-6.84 (m, 4H) 4.52-4.65 (m, 2 H) 3.66-3.71(m, 3H) 3.46-3.53 (m, 1H) 3.25-3.28 (m, 3H) 3.09-3.17 (m, 1H) 2.37 -2.46(m, 2H) 1.33-1.40 (m, 1H) 0.98-1.04 (m, 1H)

Preparation of Example 26:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(4-(trifluoromethoxy)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.6 min.;observed ion=966.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.75-8.83(m, 1H) 8.37-8.46 (m, 2H) 8.18-8.28 (m, 1H) 7.54 (d, J=8.05 Hz, 2H)7.25-7.38 (m, 2H) 6.52-6.88 (m, 4H) 4.91 (br d, J=4.47 Hz, 1H) 4.53-4.68(m, 2H) 3.63-3.72 (m, 3H) 3.53 (dd, J=14.01, 4.47 Hz, 1H) 3.25-3.28 (m,3H) 3.15-3.21 (m, 1H) 2.39-2.46 (m, 2H) 1.33-1.39 (m, 1H) 0.98-1.04 (m,1H)

Preparation of Example 27:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(difluoromethoxy)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(4-(difluoromethoxy)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(difluoromethoxy)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.5 min.;observed ion=948.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.70-8.80(m, 1H) 8.32-8.39 (m, 2H) 8.18-8.23 (m, 1H) 7.62 -7.69 (m, 2H) 7.37-7.42(m, 2H) 6.52-6.87 (m, 5H) 4.52-4.66 (m, 2H) 3.61-3.69 (m, 3 H) 3.53 (brdd, J=14.16, 4.62 Hz, 1H) 3.26 (s, 3H) 3.18-3.21 (m, 1H) 2.36-2.48 (m,2H) 1.35-1.41 (m, 1H) 1.01 (br d, J=3.87 Hz, 1H)

Preparation of Example 28:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using4-(dibutyl(pyrimidin-4-yl)stannyl)butan-1-ylium as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.32 min.;observed ion=884.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.34-9.47(m, 1H) 9.07 (d, J=5.07 Hz, 1H) 8.85-8.91 (m, 1H) 8.79 (d, J=8.35 Hz,1H) 8.65 (dd, J=5.36, 1.49 Hz, 1H) 7.26-7.34 (m, 2H) 6.54-6.82 (m, 4H)4.88-4.92 (m, 1H) 4.51-4.61 (m, 2H) 3.62-3.66 (m, 3H) 3.51 (dd, J=14.01,4.47 Hz, 1H) 3.21-3.25 (m, 3H) 3.14-3.20 (m, 1H) 2.36-2.44 (m, 2H)1.30-1.37 (m, 1H) 0.95-1.01 (m, 1H)

Preparation of Example 29:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-chloropyridin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using4-(dibutyl(5-chloropyridin-3-yl)stannyl)butan-1-ylium as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-chloropyridin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.41 min.;observed ion=917.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.30-9.44(m, 1H) 8.74-8.87 (m, 3H) 8.22-8.35 (m, 1H) 7.20 -7.36 (m, 2H) 6.49-6.85(m, 4H) 4.53-4.63 (m, 2H) 3.63 (s, 3H) 3.50 (dd, J=14.31, 3.87 Hz, 1H)3.22 (s, 3H) 3.12-3.18 (m, 1H) 2.37-2.45 (m, 2H) 1.30-1.37 (m, 1H) 0.96-1.01 (m, 1H)

Preparation of Example 30:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-fluoropyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using4-(dibutyl(6-fluoropyridin-2-yl)stannyl)butan-1-ylium as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-fluoropyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.47 min.;observed ion=901.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.77-8.85(m, 1H) 8.53-8.64 (m, 2H) 8.11-8.24 (m, 1H) 7.20 -7.35 (m, 3H) 6.53-6.82(m, 4H) 4.51-4.62 (m, 2H) 3.60-3.68 (m, 3H) 3.48-3.53 (m, 1 H) 3.22-3.23(m, 3H) 3.13-3.17 (m, 1H) 2.34-2.44 (m, 2H) 1.30-1.37 (m, 1H) 0.93 -1.01(m, 1H)

Preparation of Example 31:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methylpyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using4-(dibutyl(6-methylpyridin-2-yl)stannyl)butan-1-ylium as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methylpyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.44 min.;observed ion=897.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.75-8.83(m, 1H) 8.65-8.72 (m, 1H) 8.39-8.46 (m, 1H) 7.88 -7.98 (m, 1H) 7.41-7.45(m, 1H) 7.22-7.34 (m, 2H) 6.52-6.82 (m, 4H) 4.88-4.92 (m, 1 H) 4.50-4.63(m, 2H) 3.59-3.67 (m, 3H) 3.48-3.54 (m, 1H) 3.23 (s, 3H) 3.13-3.19 (m,1H) 2.67-2.69 (m, 3H) 2.36-2.44 (m, 2H) 1.31-1.36 (m, 1H) 0.96-1.01 (m,1H)

Preparation of Example 32:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-fluoro-4-(methylsulfonyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using(2-methyl-4-(methylsulfonyl)phenyl)boronic acid as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsuIfonamido)-1H-indazol-7-yl)-7-(2-fluoro-4-(methylsuIfonyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.39 min.;observed ion=978.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.78-8.89(m, 1H) 8.31-8.41 (m, 1H) 8.14 (dd, J=8.34, 2.09 Hz, 1 H) 7.92-8.07 (m,2H) 7.23-7.38 (m, 2H) 6.52-6.84 (m, 4H) 4.90 (br s, 1H) 4.47-4.64 (m,2H) 3.59-3.68 (m, 3H) 3.45-3.54 (m, 1H) 3.26 (s, 3H) 3.22 (s, 3H)3.13-3.18 (m, 1H) 2.37-2.47 (m, 2H) 1.31-1.38 (m, 1H) 0.96-1.01 (m, 1H)

Preparation of Example 33:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridazin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using4-(dibutyl(pyridazin-4-yl)stannyl)butan-1-ylium as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridazin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.23 min.;observed ion=884.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.99-10.15(m, 1H) 9.41-9.56 (m, 1H) 8.81-8.96 (m, 1H) 8.48 -8.58 (m, 1H) 8.39-8.44(m, 1H) 7.25-7.39 (m, 2H) 6.48-6.84 (m, 4H) 4.49-4.66 (m, 2 H) 3.60-3.71(m, 3H) 3.47-3.54 (m, 1H) 3.24 (s, 3H) 3.14-3.20 (m, 1H) 2.37-2.44 (m,2H) 1.37-1.41 (m, 1H) 0.96-1.01 (m, 1H)

Preparation of Example 34:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure G using4-(dibutyl(pyridin-4-yl)stannyl)butan-1-ylium as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.2 min.;observed ion=883.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.75-8.86(m, 3H) 8.26-8.33 (m, 3H) 7.25-7.33 (m, 2H) 6.51-6.82 (m, 4H) 4.89-4.91(m, 1H) 4.51-4.64 (m, 2H) 3.60-3.71 (m, 3H) 3.45-3.57 (m, 1H) 3.23 (s,3H) 3.12-3.20 (m, 1 H) 2.36-2.46 (m, 2H) 1.31-1.36 (m, 1H) 0.95-1.01 (m,1H).

Preparation of Example 35:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(methylsuIfonyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure E using(4-(methylsulfonyl)phenyl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(methylsulfonyl)phenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method D: retention time=2.82 min.;observed ion=960 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.77-8.84(m, 1H) 8.48-8.55 (m, 2H) 8.26-8.31 (m, 1H) 8.15 -8.22 (m, 2H) 7.24-7.32(m, 2H) 6.52-6.82 (m, 4H) 4.51-4.63 (m, 2H) 3.60-3.66 (m, 3 H) 3.47-3.54(m, 1H) 3.20-3.25 (m, 6H) 3.12-3.19 (m, 1H) 2.35-2.44 (m, 2H) 1.31 -1.38(m, 1H) 0.96-1.02 (m, 1H)

Preparation of Example 36:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure H using2-chloro-3-fluoro-6-(trifluoromethyl)pyridine as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.477 min.;observed ion=969.2 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=8.92-8.86 (m, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.10 (d, J=6.3 Hz, 2H),7.34-7.27 (m, 2H), 6.77 (br d, J=5.4 Hz, 4H), 4.95-4.92 (m, 1H),4.61-4.54 (m, 2H), 3.65 (s, 3H), 3.54-3.43 (m, 1H), 3.23 (s, 3H),2.43-2.37 (m, 2H), 1.42-1.28 (m, 2H), 1.02-0.96 (m, 1H)

Preparation of Example 37:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(2-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure H using4-chloro-2-(trifluoromethyl)pyrimidine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(2-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.471 min.;observed ion=952.2 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=9.27 (d, J=4.8 Hz, 1H), 8.92 (d, J=7.9 Hz, 1H), 8.84 -8.79 (m,2H), 7.34-7.29 (m, 2H), 6.79-6.76 (m, 1H), 6.67-6.59 (m, 3H), 4.84-4.81(m, 1H), 4.55 (d, J=6.9 Hz, 1H), 3.65 (s, 3H), 3.55-3.49 (m, 1H), 3.23(s, 3H), 3.18-3.16 (m, 1H), 2.44-2.37 (m, 2H), 1.37-1.30 (m, 2H),1.01-0.96 (m, 1H)

Preparation of Example 38:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-(difluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure H using2-bromo-6-(difluoromethyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-(difluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.464 min.;observed ion=933.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 0.01-0.07(m, 1H) 0.97-1.00 (m, 1H) 1.34 (br d, J=5.96 Hz, 1H) 2.40 (br dd,J=6.26, 3.58 Hz, 2H) 3.14-3.20 (m, 1H) 3.23 (s, 3H) 3.47-3.56 (m, 1H)3.65 (s, 3H) 4.49-4.62 (m, 2H) 6.54-7.00 (m, 5H) 7.27-7.32 (m, 2H) 7.87(d, J=7.75 Hz, 1H) 8.24 (t, J=7.75 Hz, 1H) 8.75-8.79 (m, 2H) 8.82 (t,J=8.20 Hz, 1H)

Preparation of Example 39:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(difluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure H using2-chloro-4-(difluoromethyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-(difluoromethyl)pyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.448 min.;observed ion=933.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 0.97-1.00(m, 1H), 1.31-1.36 (m, 1H), 2.37-2.43 (m, 2H), 3.14-3.21 (m, 1H), 3.23(s, 3H), 3.46-3.55 (m, 1H), 3.65 (s, 3H), 4.50-4.63 (m, 2H), 4.91-4.93(m, 1H), 6.53-6.79 (m, 4H), 7.02 (t, J=55.43 Hz, 1H), 7.28-7.33 (m, 2H),7.71 (d, J=5.09 Hz, 1H), 8.70-8.86 (m, 3H), 8.93 (dd, J=5.07, 0.60 Hz,1H)

Preparation of Example 47:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(tributylstannyl)pyrimidine as the coupling partner. The experimentafforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.295 min.;observed ion=884.4 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=9.12 (d, J=4.8 Hz, 2H), 8.90 (d, J=8.0 Hz, 1H), 8.83 (d, J=8.0 Hz,1H), 7.68 (t, J=4.9 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.27 (d, J=7.7 Hz,1H), 6.83-6.77 (m, 1H), 6.69-6.62 (m, 2H), 6.69 (br t, J=54.7 Hz, 1H),4.94-4.91 (m, 1H), 4.65-4.57 (m, 2H), 3.67 (s, 3H), 3.55-3.47 (m, 1H),3.28-3.24 (m, 3H), 3.21-3.14 (m, 1H), 2.46-2.39 (m, 2H), 1.33-1.25 (m,1H), 1.04-0.99 (m, 1H)

Preparation of Example 48:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methylpyridin-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-methyl-4-(tributylstannyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methylpyridin-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.111 min.;observed ion=895.4 (M-H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=8.77 (d, J=8.3 Hz, 1H), 8.74 (d, J=4.8 H, 1H), 8.03 (d, J=8.3 Hz,1H), 7.97 (s, 1H), 7.83 (dd, J=1.6, 5.2 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H),6.98 (d, J=8.3 Hz, 1H), 6.74-6.69 (m, 1H), 6.65 (t, J=54.8 Hz, 1H), 6.52(d, J=7.7 Hz, 1H), 6.42 (d, J=6.3 Hz, 2H), 4.88 (q, J=7.7 Hz, 1H), 4.61(s, 2H), 3.60 (s, 3H), 3.39-3.33 (m, 4H), 3.02 (dd, J=7.9, 13.9 Hz, 1H),2.74 (s, 3H), 2.48-2.38 (m, 2H), 1.47-1.32 (m, 2H), 1.16 -1.09 (m, 1H)

Preparation of Example 49:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methylpyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using4-methyl-2-(tributylstannyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsuIfonamido)-1H-indazol-7-yl)-7-(4-methylpyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. The sample wasanalyzed using LCMS Method B: retention time=1.413 min.; observedion=897.4 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift (ppm)=8.76-8.71(m, 2H), 8.65 (d, J=5.1 Hz, 1H), 8.53 (s, 1H), 7.31-7.28 (m, 1H),7.14-7.11 (m, 1H), 7.05-6.99 (m, 1H), 6.80-6.55 (m, 3H), 6.41 (br d,J=5.7 Hz, 2H), 4.91-4.86 (m, 1H), 4.61 (s, 2H), 3.60 (s, 3H), 3.40-3.32(m, 4H), 3.02 (dd, J=8.2, 13.9 Hz, 1H), 2.54 (s, 3H), 2.47-2.36 (m, 2H),1.42-1.35 (m, 1H), 1.30-1.22 (m, 1H), 1.15-1.08 (m, 1H)

Preparation of Example 50:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-chloropyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-chloro-6-(tributylstannyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-chloropyridin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.497 min.;observed ion=917.4 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=8.89 (d, J=8.3 Hz, 1H), 8.79 (d, J=8.3 Hz, 1H), 8.76 (dd, J=1.0,7.9 Hz, 1H), 8.63-8.57 (m, 2H), 8.09 (t, J=7.9 Hz, 1H), 7.88 (t, J=7.7Hz, 1H), 7.42 (dd, J=0.9, 7.7 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.99 (d,J=8.6 Hz, 1H), 6.79 -6.54 (m, 3H), 6.43 (dd, J=1.9, 7.3 Hz, 2H), 4.89(dd, J=1.0, 8.5 Hz, 1H), 4.62 (s, 2H), 3.62 (s, 3H), 3.39-3.34 (m, 4H),3.04 (dd, J=8.0, 14.0 Hz, 1H), 2.48-2.38 (m, 2H), 1.38 (br d, J=7.2 Hz,1H), 1.25 (s, 1H), 1.14-1.09 (m, 1H)

Preparation of Example 51:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methoxypyridin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using3-methoxy-5-(tributylstannyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methoxypyridin-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.313 min.;observed ion=913.4 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=8.96 (d, J=1.5 Hz, 1H), 8.75 (d, J=8.3 Hz, 1H), 8.50 (d, J=2.7Hzz, 1H), 8.06 (dd, J=1.9, 2.8 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.12 (d,J=8.0 Hz, 1H), 6.95 (br d, J=8.0 Hz, 1H), 6.76-6.50 (m, 3H), 6.43 (d,J=6.1 Hz, 2H), 4.87 (d, J=6.9 Hz, 1H), 4.61 (s, 2H), 4.03 (s, 3H), 3.61(s, 3H), 3.40-3.33 (m, 4H), 3.02 (dd, J=7.9, 13.6 Hz, 1H), 2.44 (br d,J=4.2 Hz, 2H), 1.42-1.35 (m, 1H), 1.25 (s, 1H), 1.14-1.09 (m, 1H)

Preparation of Example 52:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridin-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using3-(tributylstannyl)pyridine as the coupling partner. The experimentafforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridin-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.247 min.;observed ion=883.4 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=9.41 (d, J=2.1 Hz, 1H), 8.81 (dd, J=1.5, 4.8 Hz, 1H), 8.76 (d,J=8.3 Hz, 1H), 8.54 (td, J=2.0, 8.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H),7.54 (dd, J=5.1, 8.0 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 6.95 (d, J=8.9 Hz,1H), 6.75-6.69 (m, 1H), 6.63 (br t, J=54.8 Hz, 1H), 6.52 (d, J=7.7 Hz,1H), 6.44-6.40 (m, 2H), 4.87 (d, J=7.5 Hz, 1H), 4.61 (s, 2H), 3.61 (s,3H), 3.39 -3.33 (m, 4H), 3.03 (dd, J=7.9, 13.6 Hz, 1H), 2.44 (br dd,J=4.5, 8.3 Hz, 2H), 1.39 (br d, J=6.9 Hz, 1H), 1.25 (s, 1H), 1.14-1.10(m, 1H)

Preparation of Example 54:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methoxypyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-methoxy-6-(tributylstannyl)pyrazine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(6-methoxypyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.41 min.;observed ion=914.4 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=9.47 (s, 1H), 8.77 (d, J=8.3 Hz, 1H), 8.62 (d, J=8.3 Hz, 1H), 8.42(d, J=0.6 Hz, 1H), 7.40-7.30 (m, 1H), 7.13 (d, J=7.7 Hz, 1H), 6.94 (d,J=8.6 Hz, 1H), 6.75-6.69 (m, 1H), 6.56 (d, J=7.7 Hz, 1H), 6.64 (t,J=54.8 Hz, 1H), 6.44-6.40 (m, 2H), 4.87 (dt, J=6.6, 8.2 Hz, 1H), 4.62(s, 2H), 4.15 (s, 3H), 3.61 (s, 3H), 3.40-3.33 (m, 4H), 3.03 (dd, J=7.9,13.9 Hz, 1H), 2.51-2.41 (m, 2H), 1.43-1.38 (m, 1H), 1.14 (dt, J=1.8, 4.0Hz, 1H)

Preparation of Example 55:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-5-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using5-(tributylstannyl)pyrimidine as the coupling partner. The experimentafforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-5-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.363 min.;observed ion=884.2 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=8.85-8.80 (m, 1H), 8.77 (br d, J=5.4 Hz, 1H), 8.73 (d, J=8.3 Hz,1H), 7.32 (br s, 1H), 7.14-7.04 (m, 1H), 6.95-6.88 (m, 1H), 6.76-6.65(m, 1H), 6.74 (br t, J=55.6 Hz, 1H), 6.46-6.31 (m, 3H), 4.92-4.85 (m,1H), 4.65-4.55 (m, 2H), 4.19 (s, 3H), 3.57 (s, 2H), 3.39-3.30 (m, 4H),3.03-2.95 (m, 1H), 2.46-2.36 (m, 2H), 1.41-1.30 (m, 1H), 1.08 (br d,J=1.5 Hz, 1H)

Preparation of Example 56:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methoxypyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using4-methoxy-2-(tributylstannyl)pyrimidine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(4-methoxypyrimidin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.262 min.;observed ion=914.2 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=9.54 (s, 2H), 9.41 (s, 1H), 8.81 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.3Hz, 1H), 7.36-7.33 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.90 (d, J=8.6 Hz,1H), 6.75-6.50 (m, 3H), 6.42 (d, J=6.7 Hz, 2H), 4.86 (d, J=6.9 Hz, 1H),4.61 (d, J=1.5 Hz, 2H), 3.62 (s, 3H), 3.42-3.33 (m, 4H), 3.03 (dd,J=7.9, 13.9 Hz, 1H), 2.46 (td, J=4.2, 8.3 Hz, 2H), 1.43-1.39 (m, 1H),1.27-1.24 (m, 1H), 1.20-1.10 (m, 1H), 0.87-0.80 (m, 1H)

Preparation of Example 57:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3,5-dichloropyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using3,5-dichloro-2-(tributylstannyl)pyrazine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3,5-dichloropyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.468 min.;observed ion=952.1 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=8.83 (d, J=8.0 Hz, 1H), 8.72 (s, 1H), 8.08 (d, J=8.3 Hz, 1H),7.35-7.31 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H),6.77-6.51 (m, 3H), 6.42 (d, J=6.8 Hz, 2H), 4.90 (d, J=7.5 Hz, 1H), 4.58(s, 2H), 3.62 (s, 3H), 3.40-3.31 (m, 4H), 3.01 (dd, J=7.6, 13.9 Hz, 1H),2.47-2.38 (m, 2H), 1.25 (br d, J=1.2 Hz, 1H), 1.11-1.07 (m, 1H)

Preparation of Example 58:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(methylsulfonyl)pyrimidin-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(methylsulfonyl)-5-(tributylstannyl)pyrimidine as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(methylsulfonyl)pyrimidin-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.29 min.;observed ion=962.2 (M+H). 1H NMR (500 MHz, CDCl3, 303 K) Shift(ppm)=9.69 (s, 2H), 8.87 (d, J=8.0 Hz, 1H), 8.22 (s, 2H), 8.07 (d, J=8.0Hz, 1H), 7.34 (br s, 1H), 6.92-6.87 (m, 1H), 6.74-6.69 (m, 1H),6.60-6.56 (m, 1H), 6.42 (d, J=6.6 Hz, 2H), 4.88-4.80 (m, 1H), 4.62 (d,J=1.8 Hz, 2H), 3.63 (s, 3H), 3.48 (s, 3H), 3.41-3.35 (m, 4H), 3.06-3.00(m, 1H), 1.45-1.40 (m, 2H), 1.14 (br s, 1H), 1.04 -1.02 (m, 1H)

Preparation of Example 59:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methoxypyridin-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-methoxy-4-(tributylstannyl)pyridine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methoxypyridin-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.407 min.;observed ion=913.4 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=8.82 (d, J=8.0 Hz, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.26 (d, J=8.3 Hz,1H), 7.79 (dd, J=1.5, 5.4 Hz, 1H), 7.67 (s, 1H), 7.36-7.30 (m, 2H), 6.83-6.78 (m, 1H), 6.64 (dd, J=1.9, 7.9 Hz, 2H), 6.67 (t, J=54.8 Hz, 1H),4.97-4.91 (m, 1H), 4.64-4.58 (m, 2H), 4.05 (s, 3H), 3.66 (s, 3H), 3.52(dd, J=4.6, 14.2 Hz, 1H), 3.26 (s, 3H), 3.21-3.15 (m, 1H), 2.45-2.39 (m,2H), 1.39-1.33 (m, 1H), 1.02-0.96 (m, 1H)

Preparation of Example 60:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(tributylstannyl)pyridine as the coupling partner. The experimentafforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(pyridin-2-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.389 min.;observed ion=883.4 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=8.84-8.81 (m, 2H), 8.71-8.65 (m, 2H), 8.11-8.09 (m, 1H), 7.60 (t,J=6.3 Hz, 1H), 7.36 -7.30 (m, 2H), 6.71 (s, 4H), 4.87-4.86 (m, 1H), 4.59(d, J=8.6 Hz, 2H), 3.67 (s, 3H), 3.56 -3.51 (m, 1H), 3.26 (s, 3H),3.20-3.18 (m, 1H), 2.45-2.39 (m, 2H), 1.36 (br d, J=6.9 Hz, 1H), 1.01(s, 1H)

Preparation of Example 61:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-chloropyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-chloro-3-(tributylstannyl)pyrazine as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-chloropyrazin-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.36 min.;observed ion=918.2 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=8.90 (d, J=8.3 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.67 (d, J=2.4 Hz,1H), 8.14 (d, J=8.0 Hz, 1H), 7.37-7.30 (m, 2H), 6.82-6.63 (m, 4H),4.94-4.92 (m, 1H), 4.59-4.52 (m, 2H), 3.69 (s, 3H), 3.55-3.47 (m, 1H),3.26 (s, 3H), 3.19-3.12 (m, 1H), 2.46-2.38 (m, 2H), 1.36 (br d, J=6.0Hz, 1H), 1.00 (dt, J=1.8, 3.7 Hz, 1H)

Preparation of Example 62:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(pentafluoro-16-sulfaneyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using4,4,5,5-tetramethyl-2-(3-(pentafluoro-16-sulfaneyl)phenyl)-1,3,2-dioxaborolaneas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(pentafluoro-16-sulfaneyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.569 min.;observed ion=1008.4 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=8.87 (s, 1H), 8.82 (d, J=8.3 Hz, 1H), 8.50 (d, J=8.0 Hz, 1H), 8.31(d, J=8.3 Hz, 1H), 8.07 (dd, J=1.5, 8.3 Hz, 1H), 7.84 (t, J=8.2 Hz, 1H),7.37-7.31 (m, 2H), 6.83-6.77 (m, 1H), 6.64 (br d, J=6.6 Hz, 2H), 6.67(br t, J=54.8 Hz, 1H), 4.67-4.57 (m, 3H), 3.66 (s, 3H), 3.55-3.45 (m,1H), 3.26 (s, 3H), 3.22-3.16 (m, 1H), 2.46-2.39 (m, 2H), 1.35 (s, 1H),1.00 (br dd, J=1.0, 3.1 Hz, 1H)

Preparation of Example 63:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(pentafluoro-l6-sulfaneyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using4,4,5,5-tetramethyl-2-(4-(pentafluoro-l6-sulfaneyl)phenyl)-1,3,2-dioxaborolaneas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(pentafluoro-l6-sulfaneyl)phenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method B: retention time=1.569 min.;observed ion=1008.3 (M+H). 1H NMR (500 MHz, CD3OD, 303 K) Shift(ppm)=8.83 (d, J=8.3 Hz, 1H), 8.48 (d, J=8.6 Hz, 2H), 8.29 (d, J=8.3 Hz,1H), 8.10 (d, J=7.9 Hz, 2H), 7.35-7.29 (m, 2H), 6.83-6.78 (m, 1H), 6.65(dd, J=1.9, 7.9 Hz, 2H), 6.68 (t, J=54.8 Hz, 1H), 4.97-4.92 (m, 1H),4.64-4.55 (m, 2H), 3.67 (s, 3H), 3.53 (dd, J=4.6, 14.5 Hz, 1H), 3.26 (s,3H), 3.22-3.16 (m, 1H), 2.46-2.39 (m, 2H), 1.36 (br d, J=7.5 Hz, 1H),1.01 (td, J=2.1, 3.6 Hz, 1H)

Preparation of Example 64:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1H-imidazol-1-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

A mixture of3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (50 mg, 0.050 mmol) and 1H-imidazole (34.2 mg,0.502 mmol) in 1,2-Dimethoxyethane (DME) (1 mL) was heated at 95° C. for1 h. LCMS showed a peak with the expected M+H. The mixture wasconcentrated and the residue was dissolved in DMF, filtered, and thefiltrate was subjected to HPLC purification to afford the titlecompound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1H-imidazol-1-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.17 min.;observed ion=872.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.79-8.88(m, 2H), 8.16 (t, J=1.49 Hz, 1H), 8.03 (d, J=8.64 Hz, 1 H), 7.26-7.38(m, 3H), 6.54-6.85 (m, 4H), 4.58 (d, J=10.13 Hz, 2H), 3.67 (s, 3H), 3.47-3.55 (m, 1H), 3.26 (s, 3H), 3.13-3.21 (m, 1H), 2.37-2.48 (m, 2H), 1.36(q, J=7.25 Hz, 1 H), 0.98-1.05 (m, 1H).

Preparation of Example 65:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a solution of3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (50 mg, 0.050 mmol) and3-(trifluoromethyl)-1H-pyrazole (10.24 mg, 0.075 mmol) inN,N-Dimethylacetamide (DMA) (1 mL) was added K2CO3 (8.32 mg, 0.060 mmol)and the mixture was heated at 40° C. for 16 h. LCMS showed a peak withthe expected M+H. The mixture was filtered and the filtrate wassubjected to HPLC purification to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.53 min.;observed ion=940.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.97 (dt,J=2.76, 1.01 Hz, 1H), 8.88 (d, J=8.34 Hz, 1H), 8.34 (d, J=8.64 Hz, 1H),7.28-7.37 (m, 2 H), 7.04 (d, J=2.68 Hz, 1H), 6.55-6.85 (m, 4H), 4.56 (d,J=6.85 Hz, 2H), 3.68 (s, 3H), 3.48-3.55 (m, 1H), 3.27 (s, 3H), 3.12-3.21(m, 1H), 2.39-2.53 (m, 2H), 1.33-1.40 (m, 1 H), 0.97-1.04 (m, 1H).

Preparation of Example 66:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a solution of3-(4-chloro-1-methyl-3-(N-(methylsulfonyl)acetamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (50 mg, 0.050 mmol) and4-(trifluoromethyl)-1H-pyrazole (10.24 mg, 0.075 mmol) inN,N-Dimethylacetamide (DMA) (1 mL) was added K2CO3 (8.32 mg, 0.060 mmol)and the mixture was heated at 40° C. for 16 h. LCMS showed a peak withthe expected M+H. The mixture was filtered and the filtrate wassubjected to HPLC purification to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.53 min.;observed ion=940.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.22 -9.30(m, 1H), 8.87 (d, J=8.64 Hz, 1H), 8.35 (d, J=8.64 Hz, 1H), 8.23 (s, 1H),7.25-7.38 (m, 2H), 6.51-6.86 (m, 4H), 4.56 (d, J=7.15 Hz, 2H), 3.68 (s,3H), 3.48-3.56 (m, 1H), 3.27 (s, 3H), 3.17 (dd, J=14.16, 9.69 Hz, 1H),2.43 (ddd, J=11.25, 7.67, 4.02 Hz, 2H), 1.33-1.40 (m, 1H), 0.97-1.05 (m,1H).

Preparation of Example 67:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methylbenzo[d]thiazol-6-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using(2-methylbenzo[d]thiazol-6-yl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methylbenzo[d]thiazol-6-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.45 min.;observed ion=953.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.84-8.92(m, 1H), 8.75 (d, J=8.35 Hz, 1H), 8.41 (dd, J=8.64, 1.79 Hz, 1H), 8.27(d, J=8.64 Hz, 1H), 8.09 (d, J=8.34 Hz, 1H), 7.24-7.35 (m, 2H),6.54-6.85 (m, 4H), 4.53-4.59 (m, 2H), 3.65 (s, 3H), 3.51 (dd, J=14.16,4.62 Hz, 1H), 3.24 (s, 3H), 3.12-3.20 (m, 1H), 2.91 (s, 3H), 2.37-2.45(m, 2H), 1.31-1.37 (m, 1H), 0.94-1.02 (m, 1H).

Preparation of Example 68:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using(1-methyl-1H-pyrazol-5-yl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.36 min.;observed ion=886.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.72 (d,J=8.05 Hz, 1H), 8.04 (d, J=8.34 Hz, 1H), 7.62 (d, J=2.09 Hz, 1H),7.27-7.36 (m, 2H), 7.05 (d, J=2.09 Hz, 1H), 6.49-6.85 (m, 4H), 4.57 (d,J=8.94 Hz, 2H), 4.40 (s, 3H), 3.64 (s, 3H), 3.49 (dd, J=14.16, 4.32 Hz,1H), 3.24 (s, 3H), 3.14 (dd, J=14.16, 9.69 Hz, 1H), 2.35-2.45 (m, 2H),1.30-1.37 (m, 1H), 0.94-1.02 (m, 1H).

Preparation of Example 69:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-isobutyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using(1-isobutyl-1H-pyrazol-5-yl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-isobutyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.49 min.;observed ion=928.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.72 (d,J=8.05 Hz, 1H), 8.03 (d, J=8.34 Hz, 1H), 7.64 (d, J=2.09 Hz, 1H),7.23-7.33 (m, 2H), 7.04 (d, J=2.09 Hz, 1H), 6.51-6.82 (m, 4H), 4.66 (dd,J=13.26, 7.30 Hz, 1H), 4.45-4.56 (m, 2H), 3.67 (s, 3H), 3.53 (dd,J=14.16, 4.92 Hz, 1H), 3.25-3.27 (m, 2H), 3.24 (s, 3H), 3.11-3.16 (m,1H), 2.37-2.45 (m, 2H), 2.14-2.23 (m, 1H), 1.31-1.37 (m, 1H), 0.89 (dd,J=6.71, 1.64 Hz, 6H).

Preparation of Example 70:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using(1,3-dimethyl-1H-pyrazol-5-yl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. The sample wasanalyzed using LCMS Method H: retention time=1.37 min.; observedion=900.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.70 (d, J=8.34 Hz,1H), 7.99 (d, J=8.34 Hz, 1H), 7.29-7.37 (m, 2 H), 6.83 (d, J=0.60 Hz,1H), 6.49-6.80 (m, 4H), 4.51-4.58 (m, 2H), 4.32 (s, 3H), 3.64 (s, 3H),3.48 (dd, J=14.31, 4.77 Hz, 1H), 3.24 (s, 3H), 3.13 (dd, J=14.31, 9.84Hz, 1H), 2.36 -2.44 (m, 2H), 2.33 (s, 3H), 1.30-1.37 (m, 1H), 0.94-1.00(m, 1H).

Preparation of Example 71:N-((S)-1-(7-(benzo[d]thiazol-6-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K usingbenzo[d]thiazol-6-ylboronic acid as the coupling partner. The experimentafforded the title compound,N-((S)-1-(7-(benzo[d]thiazol-6-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.5 min.;observed ion=939.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.41 (s, 1H), 9.03 (d, J=1.79 Hz, 1H), 8.77 (d, J=8.05 Hz, 1H), 8.49 (dd, J=8.64,1.79 Hz, 1H), 8.30 (dd, J=14.90, 8.34 Hz, 2H), 7.23-7.37 (m, 2H),6.48-6.86 (m, 4H), 4.52-4.59 (m, 2H), 3.66 (s, 3H), 3.52 (dd, J=14.01,4.47 Hz, 1H), 3.24 (s, 3H), 3.17 (dd, J=14.31, 9.54 Hz, 1 H), 2.35-2.46(m, 2H), 1.31-1.38 (m, 1H), 0.95-1.03 (m, 1H).

Preparation of Example 72:N-((S)-1-(7-(benzo[d]thiazol-5-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K usingbenzo[d]thiazol-5-ylboronic acid as the coupling partner. The experimentafforded the title compound,N-((S)-1-(7-(benzo[d]thiazol-5-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.43 min.;observed ion=939.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.38 (s, 1H), 8.98 (d, J=1.49 Hz, 1H), 8.79 (d, J=8.05 Hz, 1H), 8.42 (dd, J=8.64,1.79 Hz, 1H), 8.25 -8.38 (m, 2H), 7.20-7.44 (m, 2H), 6.47-6.87 (m, 4H),4.54-4.60 (m, 2H), 3.65 (s, 3H), 3.52 (dd, J=14.45, 4.62 Hz, 1H), 3.24(s, 3H), 3.17 (dd, J=14.16, 9.69 Hz, 1H), 2.36-2.45 (m, 2H), 1.31-1.38(m, 1H), 0.97-1.02 (m, 1H).

Preparation of Example 73:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a mixture ofN-((S)-1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(25 mg, 0.025 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(29.2 mg, 0.126 mmol) in Acetonitrile (1 mL) was added cesium carbonate(12.31 mg, 0.038 mmol) and the resulting mixture was heated at 60° C.for 1 h. The mixture was cooled to room temperature, filtered, and thefiltrate was concentrated in vacuo. The residue was taken up in DCM (0.5mL) and TFA (1 mL), then to the solution was added triflic acid (0.05mL). The solution was stirred at rt for 1 h and then concentrated invacuo. The residue was dissolved in DMF (2 mL), filtered, and thefiltrate was subjected to HPLC purification to afford the titlecompound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.43 min.;observed ion=954.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.71 (d,J=8.35 Hz, 1H), 8.33 (d, J=8.35 Hz, 1H), 7.95 (d, J=2.38 Hz, 1H),7.29-7.32 (m, 1H), 7.29 (d, J=2.38 Hz, 1H), 7.24-7.27 (m, 1H), 6.45-6.86(m, 4H), 5.07-5.18 (m, 2H), 4.55 (d, J=5.96 Hz, 2H), 3.64 (s, 3H), 3.50(dd, J=14.16, 4.62 Hz, 1H), 3.23 (s, 3H), 3.09 -3.19 (m, 1H), 2.34-2.45(m, 2H), 1.32-1.37 (m, 1H), 0.95-1.03 (m, 1H).

Preparation of Example 74:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.36 min.;observed ion=912.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.60 (d,J=8.05 Hz, 1H), 8.56 (s, 1H), 8.29 (d, J=0.60 Hz, 1H), 7.94 (d, J=8.34Hz, 1H), 7.18-7.33 (m, 2H), 6.54-6.83 (m, 4H), 4.55 (d, J=3.87 Hz, 2H),3.82 (tt, J=7.30, 3.87 Hz, 1H), 3.63 (s, 3H), 3.47-3.53 (m, 1H), 3.23(s, 3H), 3.09-3.18 (m, 1H), 2.36-2.44 (m, 2H), 1.31 -1.37 (m, 2H),1.19-1.25 (m, 2H), 1.12-1.18 (m, 2H), 0.96-1.02 (m, 1H).

Preparation of Example 75:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazoleas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.4 min.;observed ion=954.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.63-8.66(m, 2H), 8.40 (s, 1H), 7.98 (d, J=8.34 Hz, 1H), 7.21-7.32 (m, 2H),6.52-6.82 (m, 4H), 5.11 (q, J=8.54 Hz, 2H), 4.55 (d, J=4.47 Hz, 2H),3.63 (s, 3H), 3.50 (dd, J=14.45, 4.62 Hz, 1H), 3.23 (s, 3H), 3.13-3.18(m, 1H), 2.31-2.47 (m, 2H), 1.32-1.37 (m, 1H), 0.95 -1.02 (m, 1H).

Preparation of Example 76:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.32 min.;observed ion=918.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.62 (d,J=8.34 Hz, 1H), 8.56 (s, 1H), 8.36 (d, J=0.60 Hz, 1H), 7.95 (d, J=8.34Hz, 1H), 7.35-7.40 (m, 1H), 7.21-7.31 (m, 2H), 6.53-6.81 (m, 4H),4.78-4.81 (m, 2H), 4.54-4.59 (m, 3 H), 3.63 (s, 3H), 3.49 (dd, J=14.16,4.32 Hz, 1H), 3.23 (s, 3H), 3.11-3.16 (m, 1H), 2.37 -2.45 (m, 2H),1.31-1.36 (m, 1H), 0.96-1.01 (m, 1H).

Preparation of Example 77:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-cyclopropyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-cyclopropyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.41 min.;observed ion=912.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 10.51-10.57 (m, 1H), 8.76 (d, J=8.34 Hz, 1H), 8.06 (d, J=8.05 Hz, 1H), 7.57(d, J=2.09 Hz, 1H), 7.27-7.37 (m, 2H), 6.96 (d, J=2.09 Hz, 1H),6.54-6.82 (m, 4H), 4.55-4.57 (m, 2H), 3.65 (s, 3H), 3.47-3.52 (m, 1H),3.24 (s, 3H), 3.08-3.14 (m, 1H), 2.35-2.47 (m, 2H), 1.31-1.37 (m, 2H),1.05-1.15 (m, 4H), 0.98 (td, J=5.89, 4.02 Hz, 1H).

Preparation of Example 78:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(cyclopropylmethyl)-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas the coupling partner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(cyclopropylmethyl)-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.45 min.;observed ion=926.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.72 (d,J=8.34 Hz, 1H), 8.04 (d, J=8.34 Hz, 1H), 7.64 (d, J=2.09 Hz, 1H),7.25-7.34 (m, 2H), 7.05 (d, J=2.09 Hz, 1H), 6.53-6.80 (m, 4H), 4.53 (s,2H), 3.66 (s, 3H), 3.51 (dd, J=13.86, 4.92 Hz, 1H), 3.23 (s, 3H),3.09-3.15 (m, 1H), 2.35-2.45 (m, 2H), 1.31-1.44 (m, 2H), 0.94-1.01 (m,1H), 0.46-0.53 (m, 2H), 0.36-0.44 (m, 2H).

Preparation of Example 79:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using2,2-difluoroethyl trifluoromethanesulfonate as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.39 min.;observed ion=936.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.69 (d,J=8.34 Hz, 1H), 8.32 (d, J=8.05 Hz, 1H), 7.89 (d, J=2.38 Hz, 1H), 7.31(br d, J=2.38 Hz, 1H), 7.23-7.26 (m, 2H), 6.61-6.78 (m, 4H), 6.21-6.44(m, 1H), 4.65-4.72 (m, 2H), 4.56 (d, J=5.96 Hz, 2H), 3.62-3.64 (m, 3H),3.48-3.52 (m, 1H), 3.23 (s, 3H), 3.13-3.16 (m, 1H), 2.38-2.43 (m, 2H),1.32-1.37 (m, 1H), 0.95 -1.02 (m, 1H).

Preparation of Example 80:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

Potassium tert-butoxide (24.70 mg, 0.220 mmol) was added to a stirredsolution of phenol (21.70 mg, 0.231 mmol) in 1,4-Dioxane (2 mL) at roomtemp and the mixture was stirred for 5 min. To the mixture was added3-(trifluoromethyl)-1H-1,2,4-triazole (43.1 mg, 0.314 mmol), Ruphos PdG3 (8.77 mg, 10.48 μmol) and3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (100 mg, 0.105 mmol). The mixture was degassed(brief high vacuum, then refilled with Ar) and the mixture was thenstirred at 80° C. for 2 h. The mixture was concentrated and the residuewas purified by prep-HPLC to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method G: retention time=1.84 min.;observed ion=941.1 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.65 (d,J=0.89 Hz, 1H), 8.93 (d, J=8.64 Hz, 1H), 8.23 (d, J=8.64 Hz, 1H), 7.31(q, J=7.95 Hz, 2H), 6.49-6.85 (m, 4H), 4.46-4.57 (m, 2H), 3.65 (s, 3H),3.49 (dd, J=14.16, 4.32 Hz, 1H), 3.24 (s, 3H), 3.15 (dd, J=14.31, 9.84Hz, 1 H), 2.41 (ddd, J=11.18, 7.60, 4.17 Hz, 2H), 1.32-1.39 (m, 1H),0.93-1.02 (m, 1H).

Preparation of Example 81:N-((S)-1-(7-(benzo[d]oxazol-5-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K usingbenzo[d]oxazol-5-ylboronic acid as the coupling partner. The experimentafforded the title compound,N-((S)-1-(7-(benzo[d]oxazol-5-yl)-(3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.4 min.;observed ion=923.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.76 (d,J=8.34 Hz, 1H), 8.69 (d, J=1.49 Hz, 1H), 8.61 (s, 1H), 8.37-8.44 (m,1H), 8.28 (d, J=8.35 Hz, 1H), 7.91 (dd, J=8.64, 0.60 Hz, 1H), 7.23-7.34(m, 2H), 6.50-6.83 (m, 4H), 4.52 -4.59 (m, 2H), 3.64 (s, 3H), 3.51 (dd,J=14.45, 4.62 Hz, 1H), 3.23 (s, 3H), 3.15-3.19 (m, 1 H), 2.35-2.46 (m,2H), 1.31-1.38 (m, 1H), 0.92-1.04 (m, 1H).

Preparation of Example 82:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methoxythiazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-methoxy-5-(tributylstannyl)thiazole as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-methoxythiazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.43 min.;observed ion=919.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.60 (d,J=8.35 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J=8.34 Hz, 1H), 7.17-7.34 (m,2H), 6.49-6.82 (m, 4H), 4.50-4.59 (m, 2H), 4.18 (s, 3H), 3.61 (s, 3H),3.46 (dd, J=14.16, 4.62 Hz, 1H), 3.23 (s, 3H), 3.12 (dd, J=14.16, 9.69Hz, 1H), 2.35-2.47 (m, 2 H), 1.29-1.40 (m, 1H), 0.91-1.03 (m, 1H).

Preparation of Example 83:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a mixture of3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (30 mg, 0.031 mmol),1-methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole (20.71 mg,0.047 mmol) and copper(I) iodide (0.599 mg, 3.14 μmol) inN,N-Dimethylformamide (DMF) (1 mL) was addedtetrakis(triphenylphosphine)palladium(0) (3.63 mg, 3.14 μmol). Themixture was then degassed (brief high vacuum, then refilled with Ar) andheated at 100° C. for 16 h. The mixture was cooled to room temperature,filtered, and the filtrate was subjected to prep-HPLC purification toafford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.52 min.;observed ion=954.2 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.78 (d,J=8.34 Hz, 1H), 8.11 (d, J=8.34 Hz, 1H), 7.43 (s, 1H), 7.30-7.37 (m,2H), 6.52-6.85 (m, 4H), 4.85-4.88 (m, 1H), 4.53-4.64 (m, 2H), 4.49 (s,3H), 3.66 (s, 3H), 3.51 (dd, J=14.31,4.47 Hz, 1H), 3.26 (s, 3H), 3.17(dd, J=14.31, 9.84 Hz, 1H), 2.38-2.47 (m, 2H), 1.33-1.39 (m, 1H),0.95-1.02 (m, 1H).

Preparation of Example 84:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,3,3-tetrafluoropropyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,3,3-tetrafluoropropyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.43 min.;observed ion=986.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.73 (d,J=8.34 Hz, 1H), 8.35 (d, J=8.34 Hz, 1H), 7.95 (d, J=2.38 Hz, 1H),7.26-7.35 (m, 3H), 6.55-6.85 (m, 4H), 6.18-6.46 (m, 1H), 5.02 (br t,J=14.01 Hz, 2H), 4.53-4.62 (m, 2H), 3.66 (s,3H), 3.52 (dd, J=14.16, 4.62Hz, 1H), 3.26 (s, 3H), 3.16-3.21 (m, 1H), 2.38-2.46 (m, 2H), 1.33-1.39(m, 1H), 0.97 -1.05 (m, 1H).

Preparation of Example 85:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using4,4,4-trifluorobutyl trifluoromethanesulfonate as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsuIfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(4,4,4-trifluorobutyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.48 min.;observed ion=982.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.71 (d,J=8.05 Hz, 1H), 8.32 (d, J=8.05 Hz, 1H), 7.86 (d, J=2.38 Hz, 1H),7.32-7.35 (m, 1H), 7.27 (d, J=8.05 Hz, 1H), 7.23 (d, J=2.38 Hz, 1H),6.56-6.83 (m, 4H), 4.53-4.62 (m, 2H), 4.34-4.44 (m, 2H), 3.66 (s, 3H),3.52 (dd, J=14.01, 4.77 Hz, 1H), 3.26 (s, 3H), 3.17-3.21 (m, 1H),2.38-2.45 (m, 2H), 2.16-2.33 (m, 5H), 1.32 -1.37 (m, 1H), 0.95-1.03 (m,1H).

Preparation of Example 86:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluorobutyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using2,2-difluorobutyl trifluoromethanesulfonate as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluorobutyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.48 min.;observed ion=964.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.72 (d,J=8.34 Hz, 1H), 8.34 (d, J=8.34 Hz, 1H), 7.89 (d, J=2.38 Hz, 1H),7.31-7.36 (m, 1H), 7.27 (dd, J=5.07, 2.68 Hz, 2H), 6.55-6.84 (m, 4H),4.76 (t, J=13.26 Hz, 2H), 4.61-4.64 (m, 1H), 4.52-4.60 (m, 2H), 3.66 (s,3H), 3.48-3.56 (m, 1 H), 3.26 (s, 3H), 3.13-3.22 (m, 1H), 2.39-2.46 (m,2H), 1.90-2.03 (m, 2H), 1.33-1.39 (m, 1H), 1.14 (t, J=7.60 Hz, 3H),0.98-1.03 (m, 1H).

Preparation of Example 87:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(3-fluoropropyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using3-fluoropropyl trifluoromethanesulfonate as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(3-fluoropropyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.41 min.;observed ion=932.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.74 (d,J=8.05 Hz, 0.4H), 8.70 (d, J=8.34 Hz, 0.6H), 8.32 (d, J=8.35 Hz, 0.6H),8.06 (d, J=8.34 Hz, 0.4H), 7.86 (d, J=2.38 Hz, 0.6H), 7.68 (d, J=2.09Hz, 0.4H), 7.25-7.36 (m, 2H), 7.22 (d, J=2.38 Hz, 0.6H), 7.09 (d, J=2.09Hz, 0.4H), 6.53-6.84 (m, 4 H), 4.99-5.13 (m, 1H), 4.55-4.59 (m, 2H),4.43-4.51 (m, 2H), 3.68 (s, 1.3H), 3.66 (s, 1.7H), 3.53 (ddd, J=14.31,9.39, 4.92 Hz, 1H), 3.27 (s, 1.3H), 3.26 (s, 1.7H), 3.12-3.21 (m, 1H),2.27-2.47 (m, 4H), 1.39 (s, 1H), 0.97-1.04 (m, 1H).

Preparation of Example 88:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.49 min.;observed ion=1004.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.73 (d,J=8.34 Hz, 1H), 8.35 (d, J=8.35 Hz, 1H), 7.98 (d, J=2.38 Hz, 1H),7.24-7.36 (m, 3H), 6.54-6.86 (m, 4H), 5.22 (t, J=14.60 Hz, 2H),4.55-4.62 (m, 2H), 3.66 (s, 3H), 3.49-3.54 (m, 1H), 3.26 (s, 3H),3.16-3.20 (m, 1H), 2.37-2.47 (m, 2H), 1.34-1.39 (m, 1H), 1.01 (qd,J=3.78, 2.09 Hz, 1H).

Preparation of Example 89:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure M using3,3,3-trifluoropropyl trifluoromethanesulfonate as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.46 min.;observed ion=968.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.74 (d,J=8.34 Hz, 0.3H), 8.71 (d, J=8.05 Hz, 0.7H), 8.33 (d, J=8.34 Hz, 0.7H),8.08 (d, J=8.34 Hz, 0.3H), 7.89 (d, J=2.09 Hz, 0.7H), 7.71 (s, 0.3H),7.10-7.37 (m, 3H), 6.56-6.84 (m, 4H), 5.11-5.33 (m, 1H), 4.47-4.64 (m,4H), 3.69 (s, 1H), 3.66 (s, 2H), 3.48-3.56 (m, 1H), 3.27 (s, 1H), 3.26(s, 2H), 3.10-3.21 (m, 1H), 2.91-3.02 (m, 2H), 2.38-2.48 (m, 2H),1.33-1.39 (m, 1H), 0.98-1.03 (m, 1H).

Preparation of Example 90:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using(5-(trifluoromethyl)-1H-pyrazol-3-yl)boronic acid as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.45 min.;observed ion=940.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.78 (d,J=8.05 Hz, 1H), 8.13-8.19 (m, 1H), 7.52 (s, 1H), 7.31-7.37 (m, 1H),7.24-7.29 (m, 1H), 6.51-6.87 (m, 4H), 4.92-4.95 (m, 1H), 4.50 (s, 2H),3.68 (s, 3H), 3.54 (dd, J=14.31, 4.47 Hz, 1H), 3.26 (s, 3H), 3.18 (dd,J=14.01, 9.54 Hz, 1 H), 2.39-2.48 (m, 2H), 1.40 (s, 1H), 0.96-1.05 (m,1H).

Preparation of Example 91:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(4-(tributylstannyl)thiazol-2-yl)propan-2-ol as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.39 min.;observed ion=947.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.77 (d,J=8.05 Hz, 1H), 8.51 (s, 1H), 8.46 (d, J=8.05 Hz, 1H), 7.31-7.35 (m,1H), 7.26-7.29 (m, 1H), 6.57-6.84 (m, 4H), 4.52-4.61 (m, 2H), 3.67 (s,3H), 3.53 (dd, J=14.16, 4.92 Hz, 1H), 3.26 (s, 3H), 3.15-3.22 (m, 1H),2.38-2.49 (m, 2H), 1.74 (s, 6H), 1.33-1.40 (m, 1H), 0.97-1.06 (m, 1H).

Preparation of Example 92:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(5-(tributylstannyl)thiazol-2-yl)propan-2-ol as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.35 min.;observed ion=947.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.69 (d,J=8.34 Hz, 1H), 8.58 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 7.32-7.36 (m,1H), 7.24-7.30 (m, 1H), 6.52-6.84 (m, 4H), 4.54-4.62 (m, 2H), 3.65 (s,3H), 3.50 (dd, J=14.01, 4.47 Hz, 1H), 3.25 (s, 3H), 3.16 (dd, J=14.31,9.84 Hz, 1H), 2.38-2.46 (m, 2H), 1.70 (s, 6H), 1.34-1.40 (m, 1H),0.98-1.04 (m, 1H).

Preparation of Example 93:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(methylsulfonyl)thiazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(methylsulfonyl)-4-(tributylstannyl)thiazole as the coupling partner.The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(methylsulfonyl)thiazol-4-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.38 min.;observed ion=967.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 9.01 (s,1H), 8.84 (d, J=8.05 Hz, 1H), 8.51 (d, J=8.34 Hz, 1H), 7.27-7.37 (m,2H), 6.54-6.84 (m, 4H), 4.50-4.61 (m, 2H), 3.67 (s, 3H), 3.53-3.56 (m,1H), 3.52 (s, 3H), 3.26 (s, 3H), 3.14-3.22 (m, 1H), 2.37-2.48 (m, 2H),1.33-1.40 (m, 1H), 0.97-1.05 (m, 1H).

Preparation of Example 94:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a mixture ofN-((S)-1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-4-oxo-7-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(80 mg, 0.075 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate(51.6 mg, 0.226 mmol) in Acetonitrile (1 mL) was added cesium carbonate(36.9 mg, 0.113 mmol) and the resulting mixture was heated at 60° C. for1 h. The mixture was then cooled to room temperature, filtered, and thefiltrate was concentrated in vacuo. The residue was taken up in DCM (0.5mL) and TFA (1 mL), and to the solution was added triflic acid (0.05mL). The solution was stirred at rt for 1 h and then concentrated invacuo. The residue was then dissolved in DMF (2 mL) and purified by prepHPLC to afford two isolates containing the target mass:

The first peak to elute was the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method D: retention time=3.3 min.;observed ion=1018 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.77 (d,J=8.05 Hz, 1H), 8.37 (d, J=8.05 Hz, 1H), 7.70 (d, J=0.60 , 1H),7.28-7.35 (m, 2H), 6.57-6.82 (m, 4H), 4.90-4.92 (m, 1H), 4.85-4.88 (m,2H), 4.54-4.61 (m, 2H), 3.66 (s, 3H), 3.52 (dd, J=14.31, 4.47Hz, 1H),3.26 (s, 3H), 3.15-3.20 (m, 1H), 2.39-2.46 (m, 2H), 1.82 (t, J=18.78 Hz,3H), 1.33-1.39 (m, 1H), 0.97-1.04 (m, 1H).

The second peak to elute was Example 95.

Preparation of Example 95:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

See preparation of Example 94 for the procedure which afforded the titlecompound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method D: retention time=3.34 min.;observed ion=1018 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.79 (d,J=8.05Hz, 1H), 8.11 (d, J=8.05 Hz, 1H), 7.50 (s, 1H), 7.31-7.36 (m, 2H),6.55-6.83 (m, 4H), 5.67-5.78 (m, 1H), 5.47-5.58 (m, 1H), 4.91-4.94 (m,1H), 4.54 (s, 2H), 3.69 (s, 3H), 3.54 (dd, J=14.16, 4.62 Hz, 1H), 3.26(s, 3H), 3.16 (dd, J=14.01, 9.54 Hz, 1H), 2.39-2.46 (m, 2H), 1.66 (t,J=18.78 Hz, 3H), 1.33-1.39 (m, 1 H), 0.97-1.02 (m, 1H).

Preparation of Example 96:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

To a mixture ofN-((S)-1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(85 mg, 0.084 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate(57.8 mg, 0.253 mmol) in Acetonitrile (2 mL) was added cesium carbonate(41.3 mg, 0.127 mmol) and the resulting mixture was heated at 60° C. for1 h. The mixture was then cooled to room temperature, filtered, and thefiltrate was concentrated in vacuo. The residue was dissolved in DCM(0.5 mL) and TFA (1 mL), then to the solution was added triflic acid(0.05 mL). The solution was stirred at rt for 1 h and then wasconcentrated in vacuo. The residue was dissolved in DMF (2 mL) and thenwas subjected to prep-HPLC purification to afford two isolatescontaining the target mass:

The first peak to elute was Example 97.

The second peak to elute was the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method D: retention time=3.13 min.;observed ion=964 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.67 (d,J=8.35 Hz, 1H), 8.28 (d, J=8.34 Hz, 1H), 7.31-7.33 (m, 1H), 7.23-7.26(m, 1H), 7.02 (s, 1H), 6.58-6.83 (m, 5H), 4.90-4.94 (m, 1H), 4.68 (t,J=12.52 Hz, 2H), 4.54-4.63 (m, 2 H), 3.65 (s, 3H), 3.50 (dd, J=14.31,4.77 Hz, 1H), 3.26 (s, 3H), 3.16 (dd, J=14.16, 9.69 Hz, 1H), 2.47 (s,3H), 2.40-2.45 (m, 2H), 1.74 (t, J=18.93 Hz, 3H), 1.36 (q, J=7.05 Hz,1H), 1.00 (br d, J=2.68Hz, 1H).

Preparation of Example 97:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-3-methyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

See preparation of Example 96 for the procedure which afforded the titlecompound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(1-(2,2-difluoropropyl)-3-methyl-1H-pyrazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method D: retention time=3.06 min.;observed ion=964.05 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.68 (d,J=8.35 Hz, 1H), 8.31 (d, J=8.35 Hz, 1H), 7.40 (d, J=7.75 Hz, 1H), 7.27(d, J=7.75 Hz, 1H), 7.05 (d, J=0.89 Hz, 1H), 6.54-6.79 (m, 4H),4.91-4.95 (m, 1H), 4.77-4.83 (m, 2H), 4.69 (t, J=12.67 Hz, 2H),3.41-3.46 (m, 1H), 3.29 (s, 3H), 3.20 (s, 3H), 3.00 (dd, J=13.41, 6.26Hz, 1H), 2.50-2.54 (m, 1H), 2.48 (s, 3 H), 1.74 (t, J=18.93 Hz, 3H),1.38-1.44 (m, 1H), 1.08-1.13 (m, 1H).

Preparation of Example 98:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure K using(5-methyl-1H-pyrazol-3-yl)boronic acid as the coupling partner. Theexperiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.31 min.;observed ion=886.4 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.69 (brd, J=8.35 Hz, 1H), 8.27 (ddd, J=5.44, 3.65, 1.94 Hz, 1H), 7.19-7.34 (m,2H), 6.98 (s, 1H), 6.51-6.84 (m, 4H), 4.50-4.67 (m, 3H), 3.65 (s, 3H),3.52 (br dd, J=13.71, 4.17 Hz, 1H), 3.24 (s, 3H), 3.14-3.20 (m, 1H),2.31-2.54 (m, 5H), 1.33-1.43 (m, 1H), 0.96-1.01 (m, 1H).

Preparation of Example 99:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(1,1-difluoroethyl)thiazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

The title compound was prepared according to General Procedure J using2-(1,1-difluoroethyl)-5-(tributylstannyl)thiazole as the couplingpartner. The experiment afforded the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(2-(1,1-difluoroethyl)thiazol-5-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method H: retention time=1.49 min.;observed ion=953.3 (M+H). 1H NMR (500 MHz, METHANOL-d4) δ ppm 8.71-8.78(m, 2H), 8.26 (d, J=8.35 Hz, 1H), 7.27-7.36 (m, 2H), 6.56-6.83 (m, 4H),4.60 (d, J=14.31 Hz, 2H), 3.65 (s, 3H), 3.50 (dd, J=14.01, 4.47 Hz, 1H), 3.25 (s, 3H), 3.15-3.20 (m, 1H), 2.39-2.46 (m, 2H), 2.19 (t, J=18.63Hz, 3H), 1.34 -1.39 (m, 1H), 0.97-1.04 (m, 1H).

Preparation of Example 100:N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methyl-1H-1,2,4-triazol-1-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

To a stirred solution of phenol (21.70 mg, 0.231 mmol) in 1,4-Dioxane (2mL) at room temp was added potassium tert-butoxide (24.70 mg, 0.220mmol) and the mixture was stirred for 5 min. To the mixture was added3-methyl-1H-1,2,4-triazole (26.1 mg, 0.314 mmol), Ruphos Pd G3 (8.77 mg,10.48 μmol) and3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yltrifluoromethanesulfonate (100 mg, 0.105 mmol). The mixture was degassed(brief high vacuum, then refilled with Ar) and then stirred at 100° C.for 2 h. The mixture was concentrated in vacuo and the resulting residuewas subjected to HPLC purification to afford the title compound,N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7-(3-methyl-1H-1,2,4-triazol-1-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.The sample was analyzed using LCMS Method D: retention time=2.88 min.;observed ion=887.0 (M+H). ¹H NMR (500 MHz, METHANOL-d₄) δ ppm 9.43 (s, 1H), 8.88 (d, J=8.64 Hz, 1H), 8.18 (d, J=8.64 Hz, 1H), 7.28-7.37 (m, 2H),6.57-6.84 (m, 4 H), 4.50-4.60 (m, 2H), 3.67 (s, 3H), 3.51 (dd, J=14.16,4.32 Hz, 1H), 3.27 (s, 3H), 3.16 (dd, J=14.01, 9.84 Hz, 1H), 2.54 (s,3H), 2.43 (ddd, J=11.40, 7.67, 4.17 Hz, 2H), 1.34 -1.39 (m, 1H),0.98-1.04 (m, 1H).

IUPAC Chemical Names:

The IUPAC chemical names for each example are listed below. At this timethese names are not recognized by common software such tools such asChemDraw or JChem. Therefore, the chemical names used throughout theExamples section above were generated with ChemDraw with P/Mnomenclature manually inserted. The chemical names can be converted tochemical structures using ChemDraw after the P/M nomenclature—e.g.,“(3P)-”—is removed.

Example IUPAC Name Example 1N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-6-[6-(trifluoromethyl)pyridin-2-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 2N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-6-[4-(difluoromethyl)pyrimidin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 3N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-6-[6-(difluoromethyl)pyridin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 4N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[2-(trifluoromethyl)-1,3-thiazol-4-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 5N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[4-(trifluoromethyl)pyrimidin-2-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 6N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[4-(difluoromethyl)pyrimidin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 7N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(3-methylpyrazin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 8N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyrazin-2-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 9N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[6-(trifluoromethyl)pyridin-2-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 10N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(4-methylpyrimidin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 11N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(4,6-dimethylpyrimidin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 12N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[6-(1,1-difluoroethyl)pyridin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 13N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[6-(trifluoromethyl)pyrazin-2-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 14N-[(1S)-1-[(3P)-7-[4,6-bis(trifluoromethyl)pyridin-2-yl]-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 15N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[6-(trifluoromethyl)pyrimidin-4-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 16N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[4-(trifluoromethyl)pyridin-2-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 17N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[5-(trifluoromethyl)pyrimidin-4-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 18N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[6-methyl-2-(trifluoromethyl)pyrimidin-4-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 19N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 20N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[3-(difluoromethoxy)phenyl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 21N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[3-(trifluoromethoxy)phenyl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 22N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[4-fluoro-2-(trifluoromethyl)phenyl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 23N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[3-(difluoromethyl)phenyl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 24N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[3-(trifluoromethyl)phenyl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 25N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[2-(trifluoromethyl)phenyl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 26N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[4-(trifluoromethoxy)phenyl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 27N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[4-(difluoromethoxy)phenyl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 28N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-4-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 29N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(5-chloropyridin-3-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 30N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(6-fluoropyridin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 31N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(6-methylpyridin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 32N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-fluoro-4-methanesulfonylphenyl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 33N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyridazin-4-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 34N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyridin-4-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 35N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(4-methanesulfonylphenyl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 36N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[3-fluoro-6-(trifluoromethyl)pyridin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 37N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[2-(trifluoromethyl)pyrimidin-4-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl] acetamide Example 38N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[6-(difluoromethyl)pyridin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 39N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[4-(difluoromethyl)pyridin-2-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 47N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-2-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 48N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-methylpyridin-4-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 49N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(4-methylpyridin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 50N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(6-chloropyridin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 51N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(5-methoxypyridin-3-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 52N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyridin-3-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 54N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(6-methoxypyrazin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 55N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyrimidin-5-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 56N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(4-methoxypyrimidin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 57N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(3,5-dichloropyrazin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 58N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-methanesulfonylpyrimidin-5-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7- yl]acetamideExample 59 N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-methoxypyridin-4-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 60N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-(pyridin-2-yl)-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 61N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(3-chloropyrazin-2-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 62N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[3-(pentafluoro-A6-sulfanyl)phenyl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 63N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[4-(pentafluoro-A6-sulfanyl)phenyl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 64N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(1H-imidazol-1-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 65N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 66N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 67N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-methyl-1,3-benzothiazol-6-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl] acetamide Example 68N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 69N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2-methylpropyl)-1H-pyrazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 70N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 71N-[(1S)-1-[(3P)-7-(1,3-benzothiazol-6-yl)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 72N-[(1S)-1-[(3P)-7-(1,3-benzothiazol-5-yl)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 73N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 74N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 75N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 76N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2-fluoroethyl)-1H-pyrazol-4-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 77N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(1-cyclopropyl-1H-pyrazol-5-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 78N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(cyclopropylmethyl)-1H-pyrazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 79N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2,2-difluoroethyl)-1H-pyrazol-3-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien- 7-yl]acetamide Example 80N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 81N-[(1S)-1-[(3P)-7-(1,3-benzoxazol-5-yl)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 82N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-methoxy-1,3-thiazol-5-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 83N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 84N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[1-(2,2,3,3-tetrafluoropropyl)-1H-pyrazol-3-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 85N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[1-(4,4,4-trifluorobutyl)-1H-pyrazol-3-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 86N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2,2-difluorobutyl)-1H-pyrazol-3-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 87N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(3-fluoropropyl)-1H-pyrazol-3-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 88N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.02,4]nona-1(6),8-dien-7- yl]acetamide Example 89N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-3-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 90N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-4-oxo-7-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 91N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[2-(2-hydroxypropan-2-yl)-1,3-thiazol-4-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 92N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 93N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(2-methanesulfonyl-1,3-thiazol-4-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 94N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2,2-difluoropropyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.02,4]nona-1(6),8-dien-7-yl]acetamide Example 95N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2,2-difluoropropyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.02,4]nona-1(6),8-dien-7-yl]acetamide Example 96N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2,2-difluoropropyl)-5-methyl-1H-pyrazol-3-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.02,4]nona-1(6),8-dien-7-yl]acetamide Example 97N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[1-(2,2-difluoropropyl)-3-methyl-1H-pyrazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.02,4]nona-1(6),8-dien-7-yl]acetamide Example 98N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-(5-methyl-1H-pyrazol-3-yl)-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide Example 99N-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-7-[2-(1,1-difluoroethyl)-1,3-thiazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide ExampleN-[(1S)-1-[(3P)-3-(4-chloro-3-methanesulfonamido-1- 100methyl-1H-indazol-7-yl)-7-[2-(1,1-difluoroethyl)-1,3-thiazol-5-yl]-4-oxo-3H,4H-pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricyclo[4.3.0.0²,⁴]nona-1(6),8-dien-7-yl]acetamide

Biological Methods:

HIV cell culture assay—MT-2 cells, 293T cells and the proviral DNA cloneof NL₄₋₃ virus were obtained from the NIH AIDS Research and ReferenceReagent Program. MT-2 cells were propagated in RPMI 1640 mediasupplemented with 10% heat inactivated fetal bovine serum (FBS), 100mg/ml penicillin G and up to 100 units/mL streptomycin. The 293T cellswere propagated in DMEM media supplemented with 10% heat inactivatedFBS, 100 mg/mL penicillin G and 100 mg/mL streptomycin. A recombinantNL₄₋₃ proviral clone, in which a section of the nef gene was replacedwith the Renilla luciferase gene, was used to make the reference virusused in these studies. The recombinant virus was prepared throughtransfection of the recombinant NL₄₋₃ proviral clone into 293T cellsusing Transit-293 Transfection Reagent from Mirus Bio LLC (Madison, WI).Supernatent was harvested after 2-3 days and the amount of virus presentwas titered in MT-2 cells using luciferase enzyme activity as a markerby measuring luciferase enzyme activity. Luciferase was quantitatedusing the EnduRen Live Cell Substrate from Promega (Madison, Wis.).Antiviral activities of compounds toward the recombinant virus werequantified by measuring luciferase activity in MT-2 cells infected for4-5 days with the recombinant virus in the presence of serial dilutionsof the compound.

The 50% effective concentration (EC₅₀) was calculated by using theexponential form of the median effect equation where(Fa)=1/[1+(ED₅₀/drug conc.)m] (Johnson VA, Byington RT. InfectivityAssay. In Techniques in HIV Research. ed. Aldovini A, Walker BD. 71-76.New York: Stockton Press. 1990). The 50% inhibitory concentration (EC₅₀)was calculated by using the exponential form of the median effectequation where percent inhibition=1/[1+(EC₅₀/drug concentration)m],where m is a parameter that reflects the slope of theconcentration-response curve.

Compound cytotoxicity and the corresponding CC₅₀ values were determinedusing the same protocol as described in the antiviral assay except thatuninfected cells were used. Cytotoxicity was assessed on day 4 inuninfected MT2 cells by using a XTT(2,3-bis[2-Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilideinner salt)-based colorimetric assay (Sigma-Aldrich, St Louis, Mo.).

Example EC₅₀ (nM) CC₅₀ (uM) Example 1 0.055 >0.1 Example 2 0.031 >0.1Example 3 0.051 >0.1 Example 4 0.055 >0.1 Example 5 0.021 >0.1 Example 60.023 >0.1 Example 7 0.020 >0.1 Example 8 0.019 >0.1 Example 90.065 >0.1 Example 10 0.030 >0.1 Example 11 0.036 >0.1 Example 120.060 >0.1 Example 13 0.040 >0.1 Example 14 0.28 >0.1 Example 150.025 >0.1 Example 16 0.052 >0.1 Example 17 0.038 >0.1 Example 180.068 >0.1 Example 19 0.23 >0.1 Example 20 0.20 >0.1 Example 210.39 >0.1 Example 22 0.052 >0.1 Example 23 0.11 >0.1 Example 240.16 >0.1 Example 25 0.060 >0.1 Example 26 0.51 >0.1 Example 270.34 >0.1 Example 28 0.040 >0.1 Example 29 0.057 >0.1 Example 300.034 >0.1 Example 31 0.031 >0.1 Example 32 0.075 >0.1 Example 330.45 >0.1 Example 34 0.070 >0.1 Example 35 0.14 >0.1 Example 360.045 >0.1 Example 37 0.11 >0.1 Example 38 0.051 >0.1 Example 390.046 >0.1 Example 47 0.067 >0.1 Example 48 0.053 >0.1 Example 490.018 >0.1 Example 50 0.056 >0.1 Example 51 0.085 >0.1 Example 520.055 >0.1 Example 54 0.039 >0.1 Example 55 0.090 >0.1 Example 560.051 >0.1 Example 57 0.073 >0.1 Example 59 0.050 >0.1 Example 600.032 >0.1 Example 61 0.025 >0.1 Example 64 0.53 >0.1 Example 650.062 >0.1 Example 66 0.070 >0.1 Example 67 0.55 >0.1 Example 680.049 >0.1 Example 69 0.099 >0.1 Example 70 0.041 >0.1 Example 710.097 >0.1 Example 72 0.11 >0.1 Example 73 0.029 >0.1 Example 740.054 >0.1 Example 75 0.090 >0.1 Example 76 0.11 >0.1 Example 770.073 >0.1 Example 78 0.090 >0.1 Example 79 0.047 >0.1 Example 800.028 >0.1 Example 81 0.082 >0.1 Example 82 0.069 >0.1 Example 830.070 >0.1 Example 84 0.041 >0.1 Example 85 0.096 >0.1 Example 860.084 >0.1 Example 87 0.036 >0.1 Example 88 0.079 >0.1 Example 890.056 >0.1 Example 90 0.098 >0.1 Example 91 0.037 >0.1 Example 920.065 >0.1 Example 93 0.056 >0.1 Example 94 0.16 >0.1 Example 950.25 >0.1 Example 96 0.044 >0.1 Example 97 12 >0.1 Example 98 0.20 >0.1Example 99 0.062 >0.1

The disclosure is not limited to the foregoing illustrative examples andthe examples should be considered in all respects as illustrative andnot restrictive, reference being made to the appended claims, ratherthan to the foregoing examples, and all changes which come within themeaning and range of equivalency of the claims are therefore intended tobe embraced.

1. A compound of Formula I, or a pharmaceutically acceptable saltthereof:

wherein: X¹ and X² are independently selected from H, F, Cl or —CH₃ andX³ is H, F, Cl, —CH₃, —OCH₃, —OCHF₂, or —OCF₃ with the proviso thatwithin the group X¹, X², and X³ the substituent Cl is not used more thantwice and the substituent —CH₃ is not used more than twice; Q isselected from:

R¹ is H, Cl, or CH₃; R² is H, C₁-C₃alkyl optionally substituted with 1-3fluorines, or C₃-C₆cycloalkyl optionally substituted with 1-2 fluorines;R³ is C₁-C₃alkyl or C₃-C₄cycloalkyl; G^(1a) is phenyl, pyridine,pyrazine or pyrimidine, each of which is substituted with —SF_(5,) orG^(1a) is selected from:

G² is C₁-C₃alkyl, —O(C₁-C₃alkyl), —S(O₂)CH₃, or —C(CH₃)₂OH whereinC₁-C₃alkyl is optionally substituted with 1-3 fluorines; G³ is H, ormethyl optionally substituted with 1-3 fluorines; G⁴ and G⁵ areindependently selected from H, —O(C₁-C₃alkyl), or C₁-C₂alkyl optionallysubstituted with 1-3 fluorines; G⁶ is H, Cl, or F; G⁷ is H, —OCH₃, or—S(O₂)CH₃; G⁸ is H, methyl, ethyl, or Cl; G⁹ is H or Cl; G¹⁰ is H,C₁-C₂alkyl, —OCH₃, or —SF5 where C₁-C₂alkyl is optionally substitutedwith 1-3 fluorines; G¹¹ and G¹² are independently selected from H, F, Clor C₁—C₂alkyl wherein C₁-C₂alkyl is optionally substituted with 1-3fluorines; G¹³ is H or F; G¹⁴ is H, methyl, Cl, —OCH₃; G¹⁵ is—O(C₁-C₂alkyl) substituted with 1-3 fluorines, or —S(O₂)CH₃; G¹⁶ isC₁-C₂alkyl or —O(C₁-C₂alkyl) wherein C₁-C₂alkyl is substituted with 1-3fluorines; G¹⁷ is H, cPr, —CH2cPr, or C₁-C₄alkyl wherein C₁-C₄alkyl isoptionally substituted with 1-5 fluorines; Y is O, S or N; G^(1b) ispyridine, pyrimidine, pyrazine, or phenyl, each of which is substitutedonce from the group F, Cl, or C₁-C₂alkyl wherein C₁-C₂alkyl isoptionally substituted with 1-3 fluorines; W is selected from:

wherein R⁴ is methyl optionally substituted with 1-3 fluorines.
 2. Acompound or salt according to claim 1 wherein Q is the following:


3. A compound or salt according to claim 1 wherein Q is the following:


4. A compound or salt according to claim 1 wherein W is the following:


5. A compound or salt according to claim 1 wherein W is the following:


6. A compound or salt according to claim 1 wherein W is the following:

wherein R⁴ is methyl optionally substituted with 1-3 fluorines.
 7. Acompound or salt according to claim 1 wherein R¹ is Cl; R² is methyl,2,2-difluoroethyl, or 2,2,2-trifluoroethyl; and R³ is methyl orcyclopropyl.
 8. A compound or salt according to claim 1 wherein R¹ isCl; R² is methyl; and R³ is methyl.
 9. A compound or salt according toclaim 1 wherein X³ is H.
 10. A compound or salt according to claim 1wherein X¹ is F, X² is F, and X³ is H.
 11. A compound or salt accordingto claim 1 wherein if X³ is H then at least one of X¹ and X² is otherthan F.
 12. A compound or salt according to claim 1 wherein G^(1a) isone of the following:


13. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


14. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


15. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


16. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


17. A compound or salt according to claim 1 wherein G^(1a) is:


18. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


19. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


20. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


21. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


22. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


23. A compound or salt according to claim 1 wherein G^(1a) is one of thefollowing:


24. A compound or salt according to claim 1 wherein G^(1b) is one of thefollowing:


25. A compound or salt according to claim 1 wherein G^(1a) or G^(1b)contains 2-3 fluorines.
 26. A compound or salt according to claim 1wherein the chemical formula of G^(1a) or G^(1b) isC₍₄₋₆₎H₍₂₋₃₎F₍₂₋₃₎N₍₁₋₂₎.
 27. A compound or salt according to claim 1wherein the stereochemistry is as depicted below:


28. A compound or salt according to claim 1 wherein the stereochemistryis as depicted below:


29. A compound or salt according to claim 1, selected from the groupconsisting of:

and pharmaceutically acceptable salts thereof.
 30. A compound or saltaccording to claim 1, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 31. A compound or saltaccording to claim 1, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 32. A compound or saltaccording to claim 1, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 33. A compound or saltaccording to claim 1, selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 34. A pharmaceuticalcomposition comprising a compound or salt according to claim
 1. 35. Acomposition according to claim 34 further comprising a pharmaceuticallyacceptable excipient.
 36. A composition according to claim 34 suitablefor oral administration, for intramuscular injection, or forsubcutaneous injection.
 37. A method of treating HIV infection in ahuman comprising administration of a compound or salt according toclaim
 1. 38. The method of claim 37 wherein said administration is oral.39. The method of claim 37 wherein said administration is intramuscularinjection or subcutaneous injection.
 40. The method of claim 37 whereinsaid method further comprises administration of at least one other agentused for treatment of HIV infection in a human.
 41. The method of claim40 wherein said at least one other agent is selected from the groupconsisting of dolutegravir, bictegravir, lamivudine, fostemsavir, andcabotegravir. 42-44. (canceled)